TAGLN

Gene Summary

Gene:TAGLN; transgelin
Aliases: SM22, SMCC, TAGLN1, WS3-10
Location:11q23.3
Summary:The protein encoded by this gene is a transformation and shape-change sensitive actin cross-linking/gelling protein found in fibroblasts and smooth muscle. Its expression is down-regulated in many cell lines, and this down-regulation may be an early and sensitive marker for the onset of transformation. A functional role of this protein is unclear. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transgelin
Source:NCBIAccessed: 09 March, 2017

Ontology:

What does this gene/protein do?
TAGLN is implicated in:
- actin binding
- cytoplasm
- muscle organ development
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 10 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TAGLN (cancer-related)

Lu Y, Li J, Cheng J, Lubahn DB
Messenger RNA profile analysis deciphers new Esrrb responsive genes in prostate cancer cells.
BMC Mol Biol. 2015; 16:21 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Orphan nuclear receptor estrogen related receptor β (Esrrb or ERRβ) is well known in stem cells and early embryonic development. However, little is known about its function in cancer.
METHOD: We investigated the mRNA profile alterations induced by Esrrb expression and its synthetic ligand DY131 in human prostate cancer DU145 cells via RNA-Seq analysis.
RESULTS: We distinguished 67 mRNAs differentially expressed by Esrrb alone. Although DY131 alone did not change any gene, treatment of DY131 in the presence of Esrrb altered 1161 mRNAs. These observations indicated Esrrb had both ligand-independent and ligand-dependent activity. When Esrrb was expressed, DY131 treatment further regulated 15 Esrrb-altered mRNAs. DY131 acted as an antagonist for 11 of 15 mRNAs (wdr52, f13a1, pxdn, spns2, loc100506599, tagln, loc441454, tkel1, sema3f, zcwpw2, sdc2) and as an agonist for 4 of the 15 mRNAs (rarres3, oasl, padi2, ddx60). Gene ontology analyses showed altered genes are related to transcription and translation regulation, cell proliferation and apoptosis regulation, and cellular metabolism.
CONCLUSION: Our results characterized mRNA profiles in DU145 prostate cancer cells driven by Esrrb expression and Esrrb ligand DY131, and provided multiple markers to characterize Esrrb's function in Esrrb research.

Li F, Wang Z, Huang Y, et al.
Delivery of PUMA Apoptosis Gene Using Polyethyleneimine-SMCC-TAT/DNA Nanoparticles: Biophysical Characterization and In Vitro Transfection Into Malignant Melanoma Cells.
J Biomed Nanotechnol. 2015; 11(10):1776-82 [PubMed] Related Publications
A synthesized PEI-based gene delivery system, wherein PEI was crosslinked with sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (Sulfo-SMCC) conjugating trans-activating transcriptional activator (TAT), yielding PEI-SMCC-TAT (PST), a novel non-viral vector for apoptosis-related gene PUMA (p53 up regulated modulator of apoptosis), was designed and evaluated. Sulfo-SMCC is a commonly used heterobifunctional crosslinker and is soluble in water, making the crosslinking easier without organic reagent like DMSO or chloroform. The PST/pDNA nanoparticles were 171.9 nm at the optimal N/P ratio (50:1). DNA complexes of all the PST conjugation had much lower toxicity and exhibited enhancement in transfection efficiency in comparison with single PEI vector. The results also showed that the transfection efficiency of PST/pEGFP nanoparticles into malignant melanoma A375 cell increased, and PST carrying PUMA gene induced the apoptosis of A375 cells. It was suggested that PST could be a promising melanoma tumor-targeting nanovector, and have a good potential in clinical application.

Yokota M, Kojima M, Higuchi Y, et al.
Gene expression profile in the activation of subperitoneal fibroblasts reflects prognosis of patients with colon cancer.
Int J Cancer. 2016; 138(6):1422-31 [PubMed] Related Publications
Tumors can create a heterogenetic tumor microenvironment. We recently identified the pathologically unique cancer microenvironment formed by peritoneal invasion (CMPI), and revealed that subperitoneal fibroblasts (SPFs) within peritoneal tissue play a crucial role in tumor progression through their interaction with cancer cells. Therefore, the genes in SPFs altered by cancer stimulation may include some biologically important factors associated with patient prognosis. In this study, we aimed to identify new biomarkers using genes specifically upregulated in SPFs by cancer-cell-conditioned medium (CCCM) stimulation (SPFs CCCM response genes; SCR genes) in colon cancer (CC). We constructed two frameworks using SCR gene data: a publicly released microarray dataset, and validation cases with freshly frozen CC samples to identify genes related to short recurrence-free survival (RFS). In the first framework, we selected differentially expressed genes between the high and low SCR gene expression groups. In the second framework, genes significantly related to short RFS were selected by univariate analysis using all SCR genes, and multivariate analysis was performed to select robust genes associated with short RFS. We identified CTGF, CALD1, INHBA and TAGLN in the first framework, and PDLIM5, MAGI1, SPTBN1 and TAGLN in the second framework. Among these seven genes, high expression of three genes (CALD1, TAGLN and SPTBN1) showed a poor prognosis in our validation cases. In a public microarray dataset, SCR gene expression was associated with the expression of ECM component, EMT, and M2-macrophage associated genes, which was concordant with the pathological features of CMPI. Thus, we successfully identified new prognostic factors.

Lee JS, Oh E, Yoo JY, et al.
Adenovirus expressing dual c-Met-specific shRNA exhibits potent antitumor effect through autophagic cell death accompanied by senescence-like phenotypes in glioblastoma cells.
Oncotarget. 2015; 6(6):4051-65 [PubMed] Free Access to Full Article Related Publications
c-Met, a cognate receptor tyrosine kinase of hepatocyte growth factor, is overexpressed and/or mutated in number of tumors. Therefore, abrogation of c-Met signaling may serve as potential therapeutic targets. In this study, we generated Ads expressing single shRNA specific to c-Met (shMet) (dl/shMet4 and dl/shMet5) or dual shRNAs specific to c-Met (dl/shMet4+5); and examined the therapeutic potential of these newly engineered Ads in targeting c-Met, and delineated their mechanism of action in vitro and in vivo. Ads expressing shMet induced knock-down in c-Met, and phenotypically resulted in autophagy-like features including appearance of membranousvacuoles, formation of acidic vesicular organelles, and cleavage and recruitment of microtubule-associated protein1 light chain 3 to autophagosomes. Ads expressing shMet also suppressed Akt phosphorylation and increased number of senescence-related gene products including SM22, TGase II, and PAI-1. These changes resulted in inhibition of cell proliferation and G2/M arrest of U343 cells. In vivo, intratumoral injection with dl/shMet4+5 resulted in a significant reduction of tumor growth with corresponding increasing overall survival. Histopathological analysis of these treated tumors revealed that Atg5 was highly up-regulated, indicating the therapeutic induction of autophagy. In sum, these results reveal that autophagic cell death induced by shMet-expressing Ads provide a novel strategy for targeting c-Met-expressing tumors through non-apoptotic mechanism of cell death.

Fisher CA, Harms PW, McHugh JB, et al.
Small cell carcinoma in the parotid harboring Merkel cell polyomavirus.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2014; 118(6):703-12 [PubMed] Related Publications
OBJECTIVE: This study aimed to document three new cases of primary small cell carcinoma (SmCC) of the parotid and examine immunohistochemical and quantitative real-time polymerase chain reaction (qPCR) data of the recently developed Merkel cell polyomavirus (MCPyV) within these tumors.
STUDY DESIGN: Immunohistochemistry for neuroendocrine markers (chromogranin A, CD56, CD57, neuron-specific enolase [NSE], thyroid transcription factor 1 [TTF-1]), epithelial markers (CK20, CK7, CAM 5.2), and MCPyV large T antigen (LTAg) were examined. qPCR and Sanger sequencing were performed to confirm the presence of the MCPyV LTAg gene.
RESULTS: Two males and one female, average age 76 years, presented with left parotid masses. Clinical examinations, histories, and imaging studies were negative for cutaneous Merkel cell carcinoma (MCC), pulmonary and extrapulmonary SmCC, or any other malignancy. Immunohistochemical analysis demonstrated positive immunoreactivity for CK20 in a perinuclear dotlike pattern (3/3), CAM 5.2 (3/3), (2/3), NSE (3/3), CD56 (2/3), and CD57 (3/3). Two cases stained positive for MCPyV, showing moderate to strong, diffuse positivity, confirmed with qPCR. PCR-Sanger sequencing of LTAg exon 2 showed greater than 97% similarity to the MCPyV reference genome in both cases.
CONCLUSION: Our findings expand the number of reported cases classified as primary parotid SmCC that harbors MCPyV and underscore the similarity between cutaneous MCC and parotid SmCC. Further investigation is needed to determine whether immune-based therapeutic strategies targeting MCPyV in MCC are also effective in the setting of parotid SmCC harboring MCPyV.

Zhao M, Huang J, Gui K, et al.
The downregulation of miR-144 is associated with the growth and invasion of osteosarcoma cells through the regulation of TAGLN expression.
Int J Mol Med. 2014; 34(6):1565-72 [PubMed] Related Publications
Alterations in the expression of microRNAs (miRNAs or miRS) have been implicated in the pathogenesis of the majority of human malignancies, and the dysregulation of microRNA-144 (miR-144) has been associated with several diseases. However, the potential involvement of miR-144 in osteosarcoma, a common malignant bone tumor in children and adolescents with a high risk of relapse and metastasis, has not yet been fully investigated. In the present study, we examined the expression and roles of miRNAs in osteosarcoma as potential diagnostic markers and therapeutic targets, and we focused on miR-144 due to its known involvement in osteogenesis. We demonstrate that miR-144 is downregulated in osteosarcoma cell lines and primary human osteosarcoma tissue samples and that its ectopic expression inhibits osteosarcoma cell proliferation and invasion. We identified TAGLN as a downstream target of miR-144 and demonstrated that its expression is upregulated in osteosarcoma cell lines and tumor tissue and is inversely correlated with miR-144 expression. Our results indicate that miR-144 may regulate osteosarcoma cell proliferation and invasion by downregulating its target gene, TAGLN, suggesting that miR-144 may be a potential therapeutic target for the treatment of osteosarcoma.

Dong W, Zhao H, Zhang C, et al.
Gene silencing of heparanase results in suppression of invasion and migration of hepatoma cells.
World J Surg Oncol. 2014; 12:85 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study investigated the effect of transcriptional gene silencing (TGS) of the heparanase gene on hepatoma SMCC-7721 cells.
METHODS: SiRNAs targeting the promoter region and coding region of the heparanase gene were designed and synthesized. Then the siRNAs were transfected into hepatoma SMCC-7721 cells by nuclear transfection or cytoplasmic transfection. The expression of heparanase was detected by RT-PCR and Western blotting 48 h, 72 h and 96 h post-transfection. In addition, wound healing and invasion assays were performed to estimate the effect of TGS of the heparanase gene on the migration and invasion of hepatoma SMCC-7721 cells.
RESULTS: Protein and mRNA expression of the heparanase gene were interfered with by TGS or post-transcriptional gene silencing (PTGS) 48 h after transfection. At 72 h post-transfection, the expression of the PTGS group of genes had recovered unlike the TGS group. At 96 h post-transfection, the expression of the heparanase gene had recovered in both the TGS group and PTGS group. Invasion and wound healing assays showed that both TGS and PTGS of the heparanase gene could inhibit invasion and migration of hepatoma SMCC-7721 cells, especially the TGS group.
CONCLUSIONS: TGS can effectively interfere with the heparanase gene to reduce the invasion and migration of hepatoma SMCC-7721 cells.

Park GH, Lee SJ, Yim H, et al.
TAGLN expression is upregulated in NF1-associated malignant peripheral nerve sheath tumors by hypomethylation in its promoter and subpromoter regions.
Oncol Rep. 2014; 32(4):1347-54 [PubMed] Free Access to Full Article Related Publications
Neurofibromatosis type 1 (NF1) caused by NF1 gene mutation is a commonly inherited autosomal dominant disorder. Malignant peripheral nerve sheath tumors (MPNSTs), a type of aggressive sarcoma, are a major cause of mortality in NF1 patients. The malignant transformation of benign plexiform neurofibromas (PNs) to MPNSTs is a marked peculiarity in NF1 patients, yet the pathogenesis remains poorly understood. We found that an actin-associated protein transgelin (SM22) was highly expressed in NF1-deficient MPNST tissues compared to NF1-deficient PN tissues using immunohistological staining and primary cultured MPNST cells in western blot analysis. We further found that this transgelin upregulation was caused by increased transcriptional expression of the TAGLN gene encoding transgelin. Comparison of DNA methylation values in the promoter and subpromoter regions of the TAGLN gene in three types of NF1-deficient primary-cultured cells, derived from an NF1 patient's normal phenotype, a benign PN and MPNST tissues, revealed that the TAGLN gene was hypomethylated in the MPNST cells. Next, to determine the functional role of transgelin in MPNST pathogenesis, we manipulated the TAGLN gene expression and investigated the alteration of the RAS-mitogen-activated protein kinase (MAPK) signaling pathway in the normal-phenotypic and malignant tumor cells. The downregulation of TAGLN expression in NF1-deficient MPNST tumor cells through the treatment of the small interfering RNA resulted in a decrease in the RAS activation (GTP-RAS) and the downstream ERK1/2 activation (phosphorylated ERK1/2), while the overexpression of TAGLN in normal-phenotypic NF1-deficient cells caused an increase in RAS and ERK1/2 activation. These results indicate that upregulation of transgelin caused by hypomethylation of the TAGLN gene is closely involved in tumor progression in NF1.

He Q, Huang Y, Cai L, et al.
Expression and prognostic value of Ars2 in hepatocellular carcinoma.
Int J Clin Oncol. 2014; 19(5):880-8 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. Arsenic resistance protein 2 (Asr2) was reported to be important for microRNA (miR) biogenesis, and its depletion could reduce the levels of several miRs, including miR-21, which is over-expressed in HCC. We hypothesized that Ars2 is also overexpressed in HCC and may be involved in the biological properties of HCC.
METHODS: Ars2 immunolabeling was evaluated in 132 HCCs. Ars2 immunolabeling, Ars2 qRT-PCR and miR-21 were evaluated in 20 HCCs and in paired normal tissues. Ars2 shRNA was transfected into SMCC-7721 and HepG2 HCC cells. The cell proliferation and expression of Ars2 and miR-21 were subsequently evaluated.
RESULTS: Ars2 was expressed primarily in the nucleus of HCC cells. The expression of Ars2 was statistically correlated with the loss of HCC differentiation and pathological stage. The survival rates of patients with low Ars2 expression in HCC were statistically higher than patients with overexpressed Ars2 in HCC. Ars2 and miR-21 were more highly expressed in HCC specimens than normal tissues, and they were also correlated. The knockdown of Ars2 in HCC cells inhibited miR-21 expression and cell proliferation.
CONCLUSIONS: Ars2 is overexpressed in HCC and may have prognostic value; it might play an important role in HCC proliferation and miR-21 expression.

Rosenberg EE, Prudnikova TY, Zabarovsky ER, et al.
D-glucuronyl C5-epimerase cell type specifically affects angiogenesis pathway in different prostate cancer cells.
Tumour Biol. 2014; 35(4):3237-45 [PubMed] Related Publications
D-glucuronyl C5-epimerase (GLCE) is involved in breast and lung carcinogenesis as a potential tumor suppressor gene, acting through inhibition of tumor angiogenesis and invasion/metastasis pathways. However, in prostate tumors, increased GLCE expression is associated with advanced disease, suggesting versatile effects of GLCE in different cancers. To investigate further the potential cancer-promoting effect of GLCE in prostate cancer, GLCE was ectopically re-expressed in morphologically different LNCaP and PC3 prostate cancer cells. Transcriptional profiles of normal PNT2 prostate cells, LNCaP, PC3 and DU145 prostate cancer cells, and GLCE-expressing LNCaP and PC3 cells were determined. Comparative analysis revealed the genes whose expression was changed in prostate cancer cells compared with normal PNT2 cells, and those differently expressed between the cancer cell lines (ACTA2, IL6, SERPINE1, TAGLN, SEMA3A, and CDH2). GLCE re-expression influenced mainly angiogenesis-involved genes (ANGPT1, SERPINE1, IGF1, PDGFB, TNF, IL8, TEK, IFNA1, and IFNB1) but in a cell type-specific manner (from basic deregulation of angiogenesis in LNCaP cells to significant activation in PC3 cells). Invasion/metastasis pathway was also affected (MMP1, MMP2, MMP9, S100A4, ITGA1, ITGB3, ERBB2, and FAS). The obtained results suggest activation of angiogenesis as a main molecular mechanism of pro-oncogenic effect of GLCE in prostate cancer. GLCE up-regulation plus expression pattern of a panel of six genes, discriminating morphologically different prostate cancer cell sub-types, is suggested as a potential marker of aggressive prostate cancer.

Fenne IS, Helland T, Flågeng MH, et al.
Downregulation of steroid receptor coactivator-2 modulates estrogen-responsive genes and stimulates proliferation of mcf-7 breast cancer cells.
PLoS One. 2013; 8(7):e70096 [PubMed] Free Access to Full Article Related Publications
The p160/Steroid Receptor Coactivators SRC-1, SRC-2/GRIP1, and SRC-3/AIB1 are important regulators of Estrogen Receptor alpha (ERα) activity. However, whereas the functions of SRC-1 and SRC-3 in breast tumourigenesis have been extensively studied, little is known about the role of SRC-2. Previously, we reported that activation of the cAMP-dependent protein kinase, PKA, facilitates ubiquitination and proteasomal degradation of SRC-2 which in turn leads to inhibition of SRC-2-coactivation of ERα and changed expression of the ERα target gene, pS2. Here we have characterized the global program of transcription in SRC-2-depleted MCF-7 breast cancer cells using short-hairpin RNA technology, and in MCF-7 cells exposed to PKA activating agents. In order to identify genes that may be regulated through PKA-induced downregulation of SRC-2, overlapping transcriptional targets in response to the respective treatments were characterized. Interestingly, we observed decreased expression of several breast cancer tumour suppressor genes (e.g., TAGLN, EGR1, BCL11b, CAV1) in response to both SRC-2 knockdown and PKA activation, whereas the expression of a number of other genes implicated in cancer progression (e.g., RET, BCAS1, TFF3, CXCR4, ADM) was increased. In line with this, knockdown of SRC-2 also stimulated proliferation of MCF-7 cells. Together, these results suggest that SRC-2 may have an antiproliferative function in breast cancer cells.

Haase R, Magnusson T, Su B, et al.
Generation of a tumor- and tissue-specific episomal non-viral vector system.
BMC Biotechnol. 2013; 13:49 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A key issue for safe and reproducible gene therapy approaches is the autologous and tissue-specific expression of transgenes. Tissue-specific expression in vivo is either achieved by transfer vectors that deliver the gene of interest into a distinct cell type or by use of tissue-specific expression cassettes. Here we present the generation of non-viral, episomally replicating vectors that are able to replicate in a tissue specific manner thus allowing tissue specific transgene expression in combination with episomal replication. The episomal replication of the prototype vector pEPI-1 and its derivatives depends exclusively on a transcription unit starting from a constitutively active promoter extending into the scaffold/matrix attachment region (S/MAR).
RESULTS: Here, we exchanged the constitutive promoter in the pEPI derivative pEPito by the tumor specific alpha fetoprotein (AFP) or the muscle specific smooth muscle 22 (SM22) promoter leading to specific transgene expression in AFP positive human hepatocellular carcinoma (HUH7) and in a SM22 positive cell line, respectively. The incorporation of the hCMV enhancer element into the expression cassette further boosted the expression levels with both promoters. Tissue specific-replication could be exemplary proven for the smooth muscle protein 22 (SM22) promoter in vitro. With the AFP promoter-driven pEPito vector hepatocellular carcinoma-specific expression could be achieved in vivo after systemic vector application together with polyethylenimine as transfection enhancer.
CONCLUSIONS: In this study we present an episomal plasmid system designed for tissue specific transgene expression and replication. The human AFP-promoter in combination with the hCMV enhancer element was demonstrated to be a valuable tissue-specific promoter for targeting hepatocellular carcinomas with non-viral gene delivery system, and tissue specific replication could be shown in vitro with the muscle specific SM22 promoter. In combination with appropriate delivery systems, the tissue specific pEPito vector system will allow higher tissue-specificity with less undesired side effects and is suitable for long term transgene expression in vivo within gene therapeutical approaches.

Terada T
Primary cutaneous small cell carcinoma; a case report with differential diagnosis.
Int J Clin Exp Pathol. 2013; 6(6):1164-8 [PubMed] Free Access to Full Article Related Publications
Primary cutaneous small cell carcinoma (PC-SmCC) is extremely rare; only two cases have been reported in the world literatures. A 79-year-old woman presented a small cutaneous tumor in the face. Physical examination showed a tumor measuring 1.0x.08x0.6 cm in the shallow skin of the face. Excisional skin biopsy was performed. The biopsy showed complete excision of the tumor. The tumor was located in the shallow dermis and no connections to epidermis were seen. The tumor was invasive into subcutaneous tissue and surrounding dermis. The tumor was very hypercellular tumor composed of small cells with scant cytoplasm, hyperchromatic nu lei, negative nucleoli, and molded nuclei. The shapes of tumor cells are round, ovoid or spindle. The histological appearances fulfilled the criteria of SmCC of WHO. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) AE1/3, CK CAM5.2, CK34BE12, CD5, CD6, CK8, p63, NSE, NCAM, synaptophysin (focal), chromogranin (focal), p53, KIT, PDGFRA and Ki-67 (labeling index (LI)=86%). They were negative for CK7, CK19, CK20, EMA, vimentin, CEA, S100 protein, CA19-9, TTF-1, MUC1, MUC2, MUC5AC and MUC6. Mucin histochemistry revealed no mucins. A molecular genetic analysis of PCR-direct sequencing identified no mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) genes. The author diagnosed this cutaneous tumor as SmCC. Post-diagnosis whole body examination using various imaging and endoscopic techniques revealed no tumors. This may confirm that the skin tumor was primary. The cutaneous tumor was completely resected with wide margins. The patient is now followed up without therapy 8 months after the diagnosis. No recurrence or metastasis is seen. The differential diagnosis from Merkel cell carcinoma and basal cell carcinoma is very difficult and herein discussed.

Terada T
Urinary bladder urothelial carcinoma with expression of KIT and PDGFRA and showing diverse differentiations into plasmacytoid, clear cell, acantholytic, nested, and spindle variants, and into adenocarcinoma, signet-ring cell carcinoma, small cell carcinoma, large cell carcinoma, and pleomorphic carcinoma.
Int J Clin Exp Pathol. 2013; 6(6):1150-6 [PubMed] Free Access to Full Article Related Publications
Various tumors can arise in the urinary bladder (UB); most common is urothelial carcinoma (UC). UC of the UB have many variants. Other types of carcinomas such as adenocarcinoma (AC) and small cell carcinoma (SmCC) can occur in UB carcinomas. Expression of KIT and PDGFRA has not been reported. A 66-year-old man admitted to our hospital because of hematuria. Cystoscopy revealed papillary invasive tumor and a transurethral bladder tumorectomy (TUR-BT) was performed. The TUR-BT showed UC, AC, SmCC, large cell carcinoma (LCC), and pleomorphic carcinoma (PC). The UC component showed plasmacytoid, spindle, nested, clear cell, acantholytic variants. The AC element showed tubular adenocarcinoma and signet-ring cell carcinoma (Sig). Immunohistochemically, all of these subtypes were positive for cytokeratin (CK) AE1/3, CK CAM5.2, CK34BE12, CK5, CK6, CK7, CK8, CK18, CK19, CK20, EMA, CEA, p63, CA19-9, p53 (positive 45%), MUC1, NSE, NCAM, KIT, PDGFRA, and Ki-67 (87%). They were negative for vimentin, chromogranin, synaptophysin, S100 protein, CD34, CD14, α-smooth muscle actin, CD31, caldesmon, CD138, CD45, κ-chain, λ-chain, MUC2, MUC5AC and MUC6. Mucin histochemistry revealed mucins in AC element including Sig. A molecular genetic analysis using PCR-direct sequencing method identified no mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) genes. The carcinoma was highly aggressive and invaded into muscular layer. The nuclear grade was very high, and there were numerous lymphovascular permeations were seen. The surface showed carcinoma in situ involving von-Brunn's nests. This case shows that carcinoma of UB can show diverse differentiations into numerous histological types and variants, and can express KIT and PDGFRA. The both genes showed no mutations in the present case.

Yuen HF, McCrudden CM, Huang YH, et al.
TAZ expression as a prognostic indicator in colorectal cancer.
PLoS One. 2013; 8(1):e54211 [PubMed] Free Access to Full Article Related Publications
The Hippo pathway restricts the activity of transcriptional coactivators TAZ (WWTR1) and YAP. TAZ and YAP are reported to be overexpressed in various cancers, however, their prognostic significance in colorectal cancers remains unstudied. The expression levels of TAZ and YAP, and their downstream transcriptional targets, AXL and CTGF, were extracted from two independent colon cancer patient datasets available in the Gene Expression Omnibus database, totaling 522 patients. We found that mRNA expressions of both TAZ and YAP were positively correlated with those of AXL and CTGF (p<0.05). High level mRNA expression of TAZ, AXL or CTGF significantly correlated with shorter survival. Importantly, patients co-overexpressing all 3 genes had a significantly shorter survival time, and combinatorial expression of these 3 genes was an independent predictor for survival. The downstream target genes for TAZ-AXL-CTGF overexpression were identified by Java application MyStats. Interestingly, genes that are associated with colon cancer progression (ANTXR1, EFEMP2, SULF1, TAGLN, VCAN, ZEB1 and ZEB2) were upregulated in patients co-overexpressing TAZ-AXL-CTGF. This TAZ-AXL-CTGF gene expression signature (GES) was then applied to Connectivity Map to identify small molecules that could potentially be utilized to reverse this GES. Of the top 20 small molecules identified by connectivity map, amiloride (a potassium sparing diuretic), and tretinoin (all-trans retinoic acid) have shown therapeutic promise in inhibition of colon cancer cell growth. Using MyStats, we found that low level expression of either ANO1 or SQLE were associated with a better prognosis in patients who co-overexpressed TAZ-AXL-CTGF, and that ANO1 was an independent predictor of survival together with TAZ-AXL-CTGF. Finally, we confirmed that TAZ regulates Axl, and plays an important role in clonogenicity and non-adherent growth in vitro and tumor formation in vivo. These data suggest that TAZ could be a therapeutic target for the treatment of colon cancer.

Davidson B, Abeler VM, Hellesylt E, et al.
Gene expression signatures differentiate uterine endometrial stromal sarcoma from leiomyosarcoma.
Gynecol Oncol. 2013; 128(2):349-55 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Endometrial stromal sarcoma (ESS) and leiomyosarcoma (LMS) are the two most common uterine sarcomas, but both are rare tumors. The aim of the present study was to compare the global gene expression patterns of ESS and LMS.
METHODS: Gene expression profiles of 7 ESS and 13 LMS were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry.
RESULTS: Unsupervised hierarchical clustering using all 54,675 genes in the array separated ESS from LMS samples. We identified 549 unique probes that were significantly differentially expressed in the two malignancies by greater than 2-fold with 1% FDR cutoff using one-way ANOVA with Benjamini-Hochberg correction, of which 336 and 213 were overexpressed in ESS and LMS, respectively. Genes overexpressed in ESS included SLC7A10, EFNB3, CCND2, ECEL1, ITM2A, NPW, PLAG1 and GCGR. Genes overexpressed in LMS included CDKN2A, FABP3, TAGLN, JPH2, GEM, NAV2 and RAB23. The top 100 genes overexpressed in LMS included those coding for myosin light chain and caldesmon, but not the genes coding for desmin or actin. CD10 was not overexpressed in ESS. Results for selected genes were validated by quantitative real-time PCR and immunohistochemistry.
CONCLUSIONS: We present the first study in which gene expression profiling was shown to distinguish between ESS and LMS. The molecular signatures unique to each of these malignancies may aid in expanding the diagnostic battery for their differentiation, and may provide a molecular basis for prognostic studies and therapeutic target discovery.

Li Q, Shi R, Wang Y, Niu X
TAGLN suppresses proliferation and invasion, and induces apoptosis of colorectal carcinoma cells.
Tumour Biol. 2013; 34(1):505-13 [PubMed] Related Publications
In order to find the correlation between transgelin gene (TAGLN) and colorectal carcinoma occurrence, we investigated the expression of TAGLN in colorectal carcinoma tissue samples and colorectal carcinoma LoVo cells. Meanwhile, the effects of TAGLN on the characteristics of LoVo cells were also examined. The expressions of TAGLN in colorectal carcinoma tissues, adjacent normal tissues, and LoVo cells were detected by the Western blot method. The recombinant plasmid pcDNA3.1-TAGLN was established and transfected into LoVo cells with the help of Lipofectamine™ 2000. At the same time, the TAGLN siRNA was transfected into LoVo cells in another group. Forty-eight hours later, the expressions of TAGLN in all groups were assayed by Western blot, and the cell viability was analyzed by MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay. The cell cycle and cell apoptosis were examined by flow cytometry, and the cell invasive ability was analyzed by Transwell invasion experiment. The effect of TALGN on the expression of matrix metalloproteinase 9 (MMP9) was detected by Western blot. Western blot analysis showed that the expressions of TALGN in colorectal carcinoma tissues and LoVo cells were significantly decreased compared with colorectal carcinoma adjacent normal tissues (p < 0.01). In the overexpression or RNAi experiments, the plasmid pcDNA3.1-TAGLN significantly enhanced TALGN expression (p < 0.01), and TAGLN siRNA significantly decreased TAGLN expression (p < 0.01) in LoVo cells 48 h after transfection. In addition, MTT assay indicated that the cell viability of LoVo cells in the pcDNA3.1-TAGLN transfection group was significantly lower than that in the untransfected control group (p < 0.05). Furthermore, the overexpression of TAGLN significantly lowered the cell proliferation index (p < 0.05) and improved cell apoptosis (p < 0.01) in LoVo cells. In Transwell invasive experiments, the cell number, which had migrated through the chamber membrane, significantly decreased in the pcDNA3.1-TAGLN transfection group (p < 0.05) and significantly increased in the TAGLN knockdown group (p < 0.05) compared to the untransfected control group. At the same time, the expression of MMP9 was notably inhibited in the pcDNA3.1-TAGLN transfection group (p < 0.01). The expressions of TAGLN were inhibited in colorectal carcinoma tissues and colorectal carcinoma LoVo cells. The study also demonstrated that TAGLN could attenuate the proliferation and invasive ability of LoVo cells and enhance LoVo cell apoptosis. Furthermore, the expression of MMP9 was also inhibited by TAGLN. All these results could bring us a new perspective for biological therapy in colorectal carcinoma.

Wickramasinghe CM, Domaschenz R, Amagase Y, et al.
HES6 enhances the motility of alveolar rhabdomyosarcoma cells.
Exp Cell Res. 2013; 319(1):103-12 [PubMed] Related Publications
HES6, a member of the hairy-enhancer-of-split family of transcription factors, plays multiple roles in myogenesis. It is a direct target of the myogenic transcription factor MyoD and has been shown to regulate the formation of the myotome in development, myoblast cell cycle exit and the organization of the actin cytoskeleton during terminal differentiation. Here we investigate the expression and function of HES6 in rhabdomyosarcoma, a soft tissue tumor which expresses myogenic genes but fails to differentiate into muscle. We show that HES6 is expressed at high levels in the subset of alveolar rhabdomyosarcomas expressing PAX/FOXO1 fusion genes (ARMSp). Knockdown of HES6 mRNA in the ARMSp cell line RH30 reduces proliferation and cell motility. This phenotype is rescued by expression of mouse Hes6 which is insensitive to HES6 siRNA. Furthermore, expression microarray analysis indicates that the HES6 knockdown is associated with a decrease in the levels of Transgelin, (TAGLN), a regulator of the actin cytoskeleton. Knockdown of TAGLN decreases cell motility, whilst TAGLN overexpression rescues the motility defect resulting from HES6 knockdown. These findings indicate HES6 contributes to the pathogenesis of ARMSp by enhancing both proliferation and cell motility.

Lu D, Burris HA, Wang B, et al.
Drug interaction potential of trastuzumab emtansine (T-DM1) combined with pertuzumab in patients with HER2-positive metastatic breast cancer.
Curr Drug Metab. 2012; 13(7):911-22 [PubMed] Related Publications
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1-related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this study and historical single-agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15-30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-agent study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.

Huang XY, Shi GM, Devbhandari RP, et al.
Low level of low-density lipoprotein receptor-related protein 1 predicts an unfavorable prognosis of hepatocellular carcinoma after curative resection.
PLoS One. 2012; 7(3):e32775 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. The aim of this study was to elucidate the expression and mechanism of LRP1 in hepatocellular carcinoma (HCC).
METHODS: LRP1 expression in 4 HCC cell lines and 40 HCC samples was detected. After interruption of LRP1 expression in a HCC cell line either with specific lentiviral-mediated shRNA LRP1 or in the presence of the LRP1-specific chaperone, receptor-associated protein (RAP), the role of LRP1 in the migration and invasion of HCC cells was assessed in vivo and in vitro, and the expression of matrix metalloproteinase (MMP) 9 in cells and the bioactivity of MMP9 in the supernatant were assayed. The expression and prognostic value of LRP1 were investigated in 327 HCC specimens.
RESULTS: Low LRP1 expression was associated with poor HCC prognosis, with low expression independently related to shortened overall survival and increased tumor recurrence rate. Expression of LRP1 in non-recurrent HCC samples was significantly higher than that in early recurrent samples. LRP1 expression in HCC cell lines was inversely correlated with their metastatic potential. After inhibition of LRP1, low-metastatic SMCC-7721 cells showed enhanced migration and invasion and increased expression and bioactivity of MMP9. Correlation analysis showed a negative correlation between LRP1 and MMP9 expression in HCC patients. The prognostic value of LRP1 expression was validated in the independent data set.
CONCLUSIONS: LRP1 modulated the level of MMP9 and low level of LRP1 expression was associated with aggressiveness and invasiveness in HCCs. LRP1 offered a possible strategy for tumor molecular therapy.

Edlund K, Lindskog C, Saito A, et al.
CD99 is a novel prognostic stromal marker in non-small cell lung cancer.
Int J Cancer. 2012; 131(10):2264-73 [PubMed] Related Publications
The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumour-stroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC and VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p = 0.037) and multivariate (p = 0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p = 0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer-associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.

Chen R, Feng C, Xu Y
Cyclin-dependent kinase-associated protein Cks2 is associated with bladder cancer progression.
J Int Med Res. 2011; 39(2):533-40 [PubMed] Related Publications
In this observational retrospective study, expression of possible cancer-related genes was measured in patients with a pathological diagnosis of superficial bladder cancer. Further measurements were made in those who subsequently developed muscle-invasive cancer. Seven of the 45 patients with superficial bladder cancer progressed to muscle-invasive cancer. Expression of fatty acid binding protein 5 (FABP5), poly(A) binding protein cytoplasmic 1 (PABPC1), DEAD box polypeptide 5 (DDX5), splicing factor 3b subunit 1 (SF3B1), murine mammary tumour integration site 6 (EIF3S6), tropomyosin 2β (TPM2), transgelin (TAGLN) and cyclin-dependent kinase-associated protein (Cks2) genes was measured in bladder samples using real-time reverse transcription-polymerase chain reaction. FABP5, PABPC1, DDX5, SF3B1, EIF3S6 and Cks2 expression levels were significantly increased, and TPM2 and TAGLN were significantly decreased, in superficial bladder cancer compared with normal bladder tissue. In patients who developed muscle-invasive cancer, the Cks2 gene showed significantly increased expression after, compared with before, invasion. The Cks2 gene may have potential as a biomarker for predicting superficial bladder cancer progression to muscle-invasive cancer.

Zhang J, Wang K, Zhang J, et al.
Using proteomic approach to identify tumor-associated proteins as biomarkers in human esophageal squamous cell carcinoma.
J Proteome Res. 2011; 10(6):2863-72 [PubMed] Free Access to Full Article Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in China. The lower survival rate of ESCC is attributed to late diagnosis and poor therapeutic efficacy; therefore, the identification of tumor-associated proteins as biomarkers for early diagnosis, and the discovery of novel targets for therapeutic intervention, seems very important for increasing the survival rate of ESCC. To identify tumor-associated proteins as biomarkers in ESCC, we have analyzed ESCC tissues and adjacent normal tissues by two-dimensional electrophoresis (2DE) and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) analysis. The results showed that a total of 104 protein spots with different expression levels were found on 2DE, and 47 proteins were eventually identified by MALDI-TOF MS. Among these identified proteins, 33 proteins including keratin 17 (KRT17), biliverdin reductase B (BLVRB), proteasome activator subunit 1 (PSME1), manganese superoxide dismutase (MnSOD), high-mobility group box-1(HMGB1), heat shock protein 70 (HSP70), peroxiredoxin (PRDX1), keratin 13 (KRT13), and so on were overexpressed, and 14 proteins including cystatin B (CSTB), tropomyosin 2 (TPM2), annexin 1 (ANX1), transgelin (TAGLN), keratin 19 (KRT19), stratifin (SFN), and so on were down-expressed in ESCC. Biological functions of these proteins are associated with cell proliferation, cell motility, protein folding, oxidative stress, and signal transduction. In the subsequent study using immunoassay on ESCC serum samples and tissue-array slides, two representative proteins, HSP70 and HMGB1, were selected as examples for the purpose of validation. The results showed that both HSP70 and HMGB1 can induce autoantibody response in ESCC sera and have higher expression in ESCC tissues. Especially, the frequency of antibodies to HSP70 in ESCC sera was significantly higher than that in normal human sera. The preliminary results suggest that some of these identified proteins might contribute to esophageal cell differentiation and carcinogenesis, certain proteins could be used as tumor-associated antigen (TAA) biomarkers in cancer diagnosis, and further studies on these identified proteins should provide more evidence of how these proteins are involved in carcinogenesis of ESCC.

Zaravinos A, Lambrou GI, Boulalas I, et al.
Identification of common differentially expressed genes in urinary bladder cancer.
PLoS One. 2011; 6(4):e18135 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Current diagnosis and treatment of urinary bladder cancer (BC) has shown great progress with the utilization of microarrays.
PURPOSE: Our goal was to identify common differentially expressed (DE) genes among clinically relevant subclasses of BC using microarrays.
METHODOLOGY/PRINCIPAL FINDINGS: BC samples and controls, both experimental and publicly available datasets, were analyzed by whole genome microarrays. We grouped the samples according to their histology and defined the DE genes in each sample individually, as well as in each tumor group. A dual analysis strategy was followed. First, experimental samples were analyzed and conclusions were formulated; and second, experimental sets were combined with publicly available microarray datasets and were further analyzed in search of common DE genes. The experimental dataset identified 831 genes that were DE in all tumor samples, simultaneously. Moreover, 33 genes were up-regulated and 85 genes were down-regulated in all 10 BC samples compared to the 5 normal tissues, simultaneously. Hierarchical clustering partitioned tumor groups in accordance to their histology. K-means clustering of all genes and all samples, as well as clustering of tumor groups, presented 49 clusters. K-means clustering of common DE genes in all samples revealed 24 clusters. Genes manifested various differential patterns of expression, based on PCA. YY1 and NFκB were among the most common transcription factors that regulated the expression of the identified DE genes. Chromosome 1 contained 32 DE genes, followed by chromosomes 2 and 11, which contained 25 and 23 DE genes, respectively. Chromosome 21 had the least number of DE genes. GO analysis revealed the prevalence of transport and binding genes in the common down-regulated DE genes; the prevalence of RNA metabolism and processing genes in the up-regulated DE genes; as well as the prevalence of genes responsible for cell communication and signal transduction in the DE genes that were down-regulated in T1-Grade III tumors and up-regulated in T2/T3-Grade III tumors. Combination of samples from all microarray platforms revealed 17 common DE genes, (BMP4, CRYGD, DBH, GJB1, KRT83, MPZ, NHLH1, TACR3, ACTC1, MFAP4, SPARCL1, TAGLN, TPM2, CDC20, LHCGR, TM9SF1 and HCCS) 4 of which participate in numerous pathways.
CONCLUSIONS/SIGNIFICANCE: The identification of the common DE genes among BC samples of different histology can provide further insight into the discovery of new putative markers.

Ruan W, Zhu S, Wang H, et al.
IGFBP-rP1, a potential molecule associated with colon cancer differentiation.
Mol Cancer. 2010; 9:281 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In our previous studies, we have demonstrated that insulin-like growth factor binding protein-related protein1 (IGFBP-rP1) played its potential tumor suppressor role in colon cancer cells through apoptosis and senescence induction. In this study, we will further uncover the role of IGFBP-rP1 in colon cancer differentiation and a possible mechanism by revealing responsible genes.
RESULTS: In normal colon epithelium, immunohistochemistry staining detected a gradient IGFBP-rP1 expression along the axis of the crypt. IGFBP-rP1 strongly expressed in the differentiated cells at the surface of the colon epithelium, while weakly expressed at the crypt base. In colon cancer tissues, the expression of IGFBP-rP1 correlated positively with the differentiation status. IGFBP-rP1 strongly expressed in low grade colorectal carcinoma and weakly expressed in high grade colorectal carcinoma. In vitro, transfection of PcDNA3.1(IGFBP-rP1) into RKO, SW620 and CW2 cells induced a more pronounced anterior-posterior polarity morphology, accompanied by upregulation with alkaline phosphatase (AKP) activity. Upregulation of carcino-embryonic antigen (CEA) was also observed in SW620 and CW2 transfectants. The addition of IGFBP-rP1 protein into the medium could mimic most but not all effects of IGFBP-rP1 cDNA transfection. Seventy-eight reproducibly differentially expressed genes were detected in PcDNA3.1(IGFBP-rP1)-RKO transfectants, using Affymetrix 133 plus 2.0 expression chip platform. Directed Acyclic Graph (DAG) of the enriched GO categories demonstrated that differential expression of the enzyme regulator activity genes together with cytoskeleton and actin binding genes were significant. IGFBP-rP1 could upreguate Transgelin (TAGLN), downregulate SRY (sex determining region Y)-box 9(campomelic dysplasia, autosomal sex-reversal) (SOX9), insulin receptor substrate 1(IRS1), cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B), amphiregulin(schwannoma-derived growth factor) (AREG) and immediate early response 5-like(IER5L) in RKO, SW620 and CW2 colon cancer cells, verified by Real time Reverse Transcription Polymerase Chain Reaction (rtRT-PCR). During sodium butyrate-induced Caco2 cell differentiation, IGFBP-rP1 was upregulated and the expression showed significant correlation with the AKP activity. The downregulation of IRS1 and SOX9 were also induced by sodium butyrate.
CONCLUSION: IGFBP-rP1 was a potential key molecule associated with colon cancer differentiation. Downregulation of IRS1 and SOX9 may the possible key downstream genes involved in the process.

Yeo M, Park HJ, Kim DK, et al.
Loss of SM22 is a characteristic signature of colon carcinogenesis and its restoration suppresses colon tumorigenicity in vivo and in vitro.
Cancer. 2010; 116(11):2581-9 [PubMed] Related Publications
BACKGROUND: We previously found the down-expression of SM22 in an experimental animal model of colorectal cancer by performing a proteomic analysis. In this study, we addressed the expression and molecular mechanisms of SM22 in human colorectal cancer.
METHODS: To evaluate the expression of SM22 in colon cancers, Western blot and immunohistochemistry were performed in 13 normal, 14 adenomas, and 44 adenocarcinomas. To address the role of SM22 in colon carcinogenesis, SM22 was restored in the colon cancer cells by the transfection with the pIRES2 vector containing full-length SM22 cDNA and tested for tumorigenicity in vivo and in vitro.
RESULTS: SM22 was found to be significantly down-regulated in adenocarcinoma (58%) compared with adenoma (21.4%) and normal (15.3%). The loss of SM22 correlated with poor differentiation of tumor (P = 0.009) and lymph node metastasis (P = 0.029). Restoration of SM22 expression inhibited cell migration, colony-forming ability of cancer cells, and induced retardation of in vivo tumor growth in a xenograft model.
CONCLUSIONS: Loss of SM22 is a molecular signature of colon cancer and is closely associated with progression, differentiation, and metastasis of colon cancer. The restoration of SM22 leads to an inhibition of colon carcinogenesis in vivo and in vitro, suggesting that SM22 might potentially function as a novel tumor suppressor.

Prasad PD, Stanton JA, Assinder SJ
Expression of the actin-associated protein transgelin (SM22) is decreased in prostate cancer.
Cell Tissue Res. 2010; 339(2):337-47 [PubMed] Related Publications
Transgelin is an actin-binding protein shown to be tumour-suppressive. Loss of transgelin expression in transformed cells is associated with oncogenesis. This study aimed to determine whether transgelin expression was suppressed in prostate cancer. An in silico meta-analysis with public-domain expressed-sequence-tag libraries of normal human prostate epithelium, prostatic intraepithelial neoplasia, invasive carcinoma and metastasised lesions predicted decreased transgelin expression with disease progression. Similarly, analysis of Affymetrix gene chip data and the Oncomine database indicated that transgelin was one the 2% most significant of all down-regulated genes in response to prostate cancer. Analysis by quantitative reverse transcription with the polymerase chain reaction (qRT-PCR) of patient biopsies determined transgelin expression to be significantly lower in prostate tumour tissue than in matched normal tissue. Similarly, qRT-PCR and Western blot analysis of representative prostate cancer cell lines demonstrated significantly lower levels of transgelin mRNA and protein in all but the DU145 prostate cancer cell line. Increased expression of TAGLN and increased transgelin protein in response to treatment with transforming growth factor-beta suggested that reduced expression in prostate cancer was not attributable to gene promoter suppression by hypermethylation. Gene ontology function analysis highlighted the importance of transgelin in the co-deregulation of actin-binding proteins. Thus, transgelin is suppressed during prostate cancer progression and seems to be an important factor in the dysregulation of the actin cytoskeleton.

Rho JH, Roehrl MH, Wang JY
Tissue proteomics reveals differential and compartment-specific expression of the homologs transgelin and transgelin-2 in lung adenocarcinoma and its stroma.
J Proteome Res. 2009; 8(12):5610-8 [PubMed] Free Access to Full Article Related Publications
Discovery of tissue-specific biomarkers for human cancer is crucial for early diagnosis and molecular understanding of the disease. To overcome the limitations posed by the large dynamic concentration range and compositional complexity of tissue biomacromolecules, we applied heparin affinity fractionation for proteomic enrichment. Comparing the proteomes of five paired samples of normal lung and pulmonary adenocarcinoma tissue by 2-D difference gel electrophoresis, 14 spots were found to be differentially expressed. From these candidate spots, three proteins overexpressed in cancer were identified by mass spectrometry as transgelin (TAGLN, SM22-alpha, WS3-10), transgelin-2 (TAGLN2), and cyclophilin A (PPIA). Quantitative RT-PCR indicated that both TAGLN2 and PPIA were upregulated at the transcriptional level. Differential protein expression levels were validated by Western blot analysis using an independent set of 10 paired lung adenocarcinoma samples. Using immunohistochemistry on human tissue sections, we discovered that overexpression of TAGLN was strictly localized to the tumor-induced reactive myofibroblastic stromal tissue compartment, whereas overexpression of TAGLN2 was exclusively localized to the neoplastic glandular compartment. Thus, the highly homologous protein pair TAGLN and TAGLN2 displayed mutually exclusive, compartment-specific cell type expression regulation in tumor stroma vs neoplastic epithelial cells. Our data further suggest that TAGLN may be a marker of active stromal remodeling in the vicinity of invasive carcinomas. It may shed light on mechanisms of tumor-stroma interaction and could be useful for early diagnosis, treatment guidance, and treatment response monitoring.

Arslan S, Silig Y, Pinarbasi H
An investigation of the relationship between SULT1A1 Arg(213)His polymorphism and lung cancer susceptibility in a Turkish population.
Cell Biochem Funct. 2009; 27(4):211-5 [PubMed] Related Publications
Human sulfotransferase 1A1 (SULT1A1), the most expressed isoform of the phenol SULT1 subfamily, is an important member of sulfotransferase superfamily. A transition, G to A at position 638, in SULT1A1 gene, results in Arg(213)His change. This single nucleotide polymorphism reduces the activity and thermostability of SULT1A1 enzyme. Thus, in the present study the relationship between SULT1A1 Arg(213)His polymorphism and lung cancer was investigated. One hundred and six case and 271 control samples were studied using PCR-RFLP. There was no significant difference in genotype and allele distribution between lung cancer and control populations (p = 0.07; p = 0.06, respectively). Compared with the SULT1A1*1/SULT1A1*1 genotype the variant SULT1A1 genotype (SULT1A1*1/SULT1A1*2 or SULT1A1*2/SULT1A1*2) was associated with a significantly increased lung cancer risk in cases (p = 0.027). In male populations, there was no significant difference between case and controls (p = 0.313). In female populations, however, this difference was found to be significant (p = 0.04). In smoker and non-smoker populations, no significant relationship was evident between lung cancer and control population (p = 0.170, p = 0.065, respectively). Statistical analyses of histological types of lung cancer in comparison with the control individuals indicated a significant difference between SULT1A1 Arg(213)His polymorphism and SCC (p = 0.027) and other types of cancer (p = 0.037), except SMCC (p = 0.854).

Zhao L, Wang H, Deng YJ, et al.
Transgelin as a suppressor is associated with poor prognosis in colorectal carcinoma patients.
Mod Pathol. 2009; 22(6):786-96 [PubMed] Related Publications
We performed comparative proteomic analysis of colorectal cancer to investigate potential target proteins correlated with carcinogenesis and prognosis. Among them, transgelin, a 22 kDa protein also called SM22, was identified as a novel tumor suppressor protein, but little is known about this protein in tumors so far. A remarkable reduced expression of transgelin was found in colorectal cancer samples compared with normal colorectal mucosa. The effect of 5-aza-2'-deoxycytidine as a demethylation agent would obviously restore the original expression level of transgelin, implicating DNA hypermethylation of transgelin is important in the regulation of transgelin transcription in colorectal cancer. As a control, the investigation at cell line level confirms that transgelin protein comes from epithelium but not mesenchymal cells. Further, immunohistochemical staining for transgelin was performed on paraffin sections of 62 and 126 cases of normal colorectal mucosa and colorectal cancer specimens, respectively. As compared to normal colorectal tissue, we observed a significantly lower transgelin expression in colorectal cancer samples (P<0.001). Survival analysis demonstrated that patients without transgelin expression had shorter overall survival, whereas patients with transgelin expression had better survival (P=0.006). Multivariate analysis showed that negative transgelin expression was an independent prognostic indicator for patient's survival. Our results suggest that transgelin as a suppressor may serve as important biomarker of malignancy. Loss of transgelin involves gene promoter hypermethylation and is closely associated with poor overall survival in colorectal cancer patients.

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