Gene Summary

Gene:TWIST1; twist family bHLH transcription factor 1
Aliases: CRS, CSO, SCS, ACS3, CRS1, BPES2, BPES3, TWIST, bHLHa38
Summary:Basic helix-loop-helix (bHLH) transcription factors have been implicated in cell lineage determination and differentiation. The protein encoded by this gene is a bHLH transcription factor and shares similarity with another bHLH transcription factor, Dermo1. The strongest expression of this mRNA is in placental tissue; in adults, mesodermally derived tissues express this mRNA preferentially. Mutations in this gene have been found in patients with Saethre-Chotzen syndrome. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:twist-related protein 1
Source:NCBIAccessed: 15 March, 2017


What does this gene/protein do?
Show (57)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 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.

  • Nuclear Proteins
  • DNA Methylation
  • Sensitivity and Specificity
  • Cell Movement
  • Survival Rate
  • Western Blotting
  • Repressor Proteins
  • Neoplasm Invasiveness
  • Biomarkers, Tumor
  • Apoptosis
  • TWIST1
  • Oligonucleotide Array Sequence Analysis
  • Oral Cavity Cancer
  • Cadherins
  • Xylenes
  • Young Adult
  • RNA Interference
  • Transcription Factors
  • Vimentin
  • Chromosome 7
  • Cancer Stem Cells
  • Gene Expression Profiling
  • Epithelial-Mesenchymal Transition
  • Neoplasm Metastasis
  • RNA Precursors
  • Homeodomain Proteins
  • Colorectal Cancer
  • Messenger RNA
  • Lung Cancer
  • Cell Proliferation
  • siRNA
  • Immunohistochemistry
  • Spheroids, Cellular
  • Epithelial Cells
  • Cancer Gene Expression Regulation
  • Breast Cancer
  • Squamous Cell Carcinoma
  • Down-Regulation
  • Drug Resistance
  • snail family transcription factors
  • MicroRNAs
  • Neoplastic Cell Transformation
  • Adenocarcinoma
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: TWIST1 (cancer-related)

Tang W, Ren A, Xiao H, et al.
Highly expressed NRSN2 is related to malignant phenotype in ovarian cancer.
Biomed Pharmacother. 2017; 85:248-255 [PubMed] Related Publications
Neurensin-2 (NRSN2) is a 24KD protein, which is reported located in the membrane, while its biological functions remain unknown, not to mention in the field of tumor biology. In current study, we aimed to analyze the functions of NRSN2 in ovarian cancer. We screened TCGA database and surprisingly found that its copy number and mRNA level are gained and heightened respectively in parts of serous ovarian cancer patients. In current study, both loss- and gain- function assays found that NRSN2 is associated with the malignant phenotype in ovarian cancer cells, because NRSN2 plays a remarkable role in anchorage-independent colony formation, subcutaneous tumor formation, cell invasion, and chemoresistance. Furthermore, we found that the level of NRSN2 was positively correlated with the expression of stem cell marker CD133. In addition, Wnt canonical signaling and Twist/Akt/Erk axis were also regulated by NRSN2. In conclusion, we found that a poorly studied protein, NRSN2, which is associated with the malignant phenotype of serous ovarian cancer and as a membrane protein; it could be a target for serous ovarian cancer treatment.

Zhou M, Zhang XY, Yu X
Overexpression of the long non-coding RNA SPRY4-IT1 promotes tumor cell proliferation and invasion by activating EZH2 in hepatocellular carcinoma.
Biomed Pharmacother. 2017; 85:348-354 [PubMed] Related Publications
BACKGROUND: Increasing evidences have demonstrated that the dysregulation of long non-coding RNAs (lncRNAs) may act as an important role in tumor progression. The long non-coding RNA SPRY4 intronic transcript 1 (SPRY4-IT1) has been reported in some cancer including regulating cell growth, differentiation, apoptosis, and cancer progression. However, the expression and function of SPRY4-IT1 in the progression of hepatocellular carcinoma (HCC) remain largely unknown.
METHODS: The lncRNA SPRY4-IT1 was detected by quantitative real time PCR (qRT-PCR) in HCC cell lines, CCK8 cell proliferation and transwell invasion assays were performed to detect the GC cell proliferation and invasion abilities. The protein expression of E-cadherin, Vimentin and Twist1 was analyzed by Western blotting assays. Furthermore, RNA immunoprecipitation (RIP) and Chromatin immunoprecipitation (ChIP) assays were used to analyze potential molecular mechanism of SPRY4-IT1 in HCC cells.
RESULTS: We found that SPRY4-IT1 was up-regulated in HCC cell lines. Further function analysis demonstrated that knockdown of SPRY4-IT1 significantly inhibited HCC cells proliferation and invasion, but over-expression of SPRY4-IT1 had the opposite effects on HCC cells in vitro. Moreover, our results also indicated that SPRY4-IT1 over-expression significantly promoted the epithelial-mesenchymal transition (EMT) by up-regulating the transcription factor Twist1 and EMT marker Vimentin and inhibited the E-cadherin expression in MHCC97L cell. Whereas, knockdown of SPRY4-IT1 suppressed the transcription factor Twist1 and EMT marker Vimentin and increased the E-cadherin expression in MHCC97H cells. Mechanisms investigations showed that SPRY4-IT1 interacted with the EZH2 and epigenetically repressed the E-cadherin expression. In vivo, we also demonstrated that the tumor growth was inhibited in SPRY4-IT1 knockdown group compared with the control group.
CONCLUSIONS: These results suggested that lncRNA SPRY4-IT1 might be considered as a therapeutic target in HCC.

Wang ZH, Li Z, Hu M, et al.
Ovol2 gene inhibits the Epithelial-to-Mesenchymal Transition in lung adenocarcinoma by transcriptionally repressing Twist1.
Gene. 2017; 600:1-8 [PubMed] Related Publications
BACKGROUND: Associated with recent achievements in therapy for advanced lung adenocarcinoma, there will still be an unmet medical need for effective treatment of stage IIIb/IV, and the prognosis of lung cancer is not optimistic till now.
OBJECTIVE: In order to obtain some essential evidences for a potential targeted therapy in lung adenocarcinoma, the effects of Ovol2 gene on Epithelial-to-Mesenchymal Transition (EMT) was observed and the probable mechanisms were analyzed.
METHODS: Ovol2 expression was previously evaluated by immunochemistry in lung adenocarcinoma tissue, and Ovol2 was overexpressed by lentivirus infection in A549 cells. Subsequently, the migration and invasion ability of A549 cells was tested by Transwell and Wound healing experiments. The mRNA level of genes correlated to EMT was detected by Real-time PCR, and the expression of reasonable makers was probed by Western Blot. Finally, rescue experiment, Luciferase assay, and chromatin immunoprecipitation assay were performed to explore the probable mechanisms.
RESULTS: After treated with Ovol2 overexpression, the expression level of E-cadherin was increased, while the expression level of Vimentin and Twist1 was declined not only in the mRNA level but also in the protein level. Moreover, we found that Ovol2 represses transcription of Twist1 by binding to its promoter directly. Wound healing and Transwell assays indicate that the migration and invasion ability were downregulated by Ovol2 in A549 cells.
CONCLUSION: Ovol2 can suppress migration and invasion ability of A549 cells, and prevent EMT by inhibition of Twist1 transcription directly.

Ma F, Wang SH, Cai Q, et al.
Overexpression of LncRNA AFAP1-AS1 predicts poor prognosis and promotes cells proliferation and invasion in gallbladder cancer.
Biomed Pharmacother. 2016; 84:1249-1255 [PubMed] Related Publications
BACKGROUND: Long non-coding RNA actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) has been elucidated to be associated with some kinds of human cancers. However, whether lncRNA AFAP1-AS1 implicates in tumor development of gallbladder cancer (GBC) remains largely unknown. This study aims to elucidate the tumorigenic role and regulatory function of lncRNA AFAP1-AS1 in gallbladder cancer.
METHODS: We analyzed lncRNA AFAP1-AS1 expression by quantitative real time PCR (qRT-PCR) in 40 gallbladder cancer tissue and adjacent normal tissues, survival plots were generated by Kaplan-Meier analysis and the log-rank test. The expression levels of transcription factor Twist1 and epithelial-to mesenchymal transition (EMT) makers (E-cadherin and Vimentin) were detected by quantitative real time PCR and western blotting analysis after knockdown of lncRNA AFAP1-AS1.
RESULTS: The expression levels of lncRNA AFAP1-AS1 were significantly elevated in GBC tissues and GBC cell lines. In addition, the expression level of lncRNA AFAP1-AS1 was significantly associated with tumor sizes and the higher expression of lncRNA AFAP1-AS1 was correlated with poor prognosis in GBC patients. Knockdown of LncRNA AFAP1-AS1 suppressed cell growth and invasion in NOZ and GBC-SD cells. Furthermore, we found that knockdown of LncRNA AFAP1-AS1 in GBC cells inhibited EMT by down-regulating the transcription factor Twist1 and Vimentin and up-regulated the E-cadherin.
CONCLUSIONS: Our results suggested lncRNA AFAP1-AS1 was correlated with poor prognosis in GBC patients and lncRNA AFAP1-AS1 might be novel therapeutic target in gallbladder cancer.

Nagai T, Arao T, Nishio K, et al.
Impact of Tight Junction Protein ZO-1 and TWIST Expression on Postoperative Survival of Patients with Hepatocellular Carcinoma.
Dig Dis. 2016; 34(6):702-707 [PubMed] Related Publications
BACKGROUND: Epithelial-mesenchymal transition (EMT) is considered to play a critical role in cancer progression and metastasis. However, the impact of EMT on the prognosis of hepatocellular carcinoma (HCC) is still elusive. In this study, we examined the relationship between the expression of EMT markers and recurrence-free survival (RFS) and overall survival (OS) in HCC patients after hepatic resection.
SUMMARY: The mRNA expression of 15 genes related to EMT was assessed by quantitative real-time polymerase chain reaction in cancerous tissues from 72 patients who underwent hepatic resection of HCC between January 2005 and December 2010 at our hospital. The upregulation of TWIST and the downregulation of tight junction protein ZO-1 (TJP1) were significantly associated with shorter RFS as well as OS. Increased levels of TWIST and decreased levels of TJP1 should be predictive markers for poor prognosis in patients with HCC after hepatectomy; those could serve as potential biomarkers for the treatment of HCC. Key Messages: A low level of TJP1 and high level of TWIST expression were prognostic factors predicting HCC after hepatic resection.

Awolaran O, Brooks SA, Lavender V
Breast cancer osteomimicry and its role in bone specific metastasis; an integrative, systematic review of preclinical evidence.
Breast. 2016; 30:156-171 [PubMed] Related Publications
Metastasis accounts for most of the deaths from breast cancer and the preference of invasive breast cancer metastasising to bone has been widely reported. However, the biological basis of breast cancer osteotropism is not fully understood. This paper provides, for the first time, an integrative, systematic review of evidence of molecular factors that have functional roles in the homing of metastatic breast cancer to the bone. Pubmed, Web of Science and EBSCOhost were searched using keywords and synonyms for molecular, metastasis, breast cancer and bone to identify articles published between January 2004 and August 2016. 4491 potentially relevant citations were retrieved. 63 articles met the inclusion criteria, which were primary studies reporting evidence of molecular factors that have functional roles in predisposing breast cancer bone metastasis in vivo. 12 of those 63 articles that additionally met quality criteria were included in the review. Extracted data were tabulated and key findings that indicated biological mechanisms involved in breast cancer metastasis to bone were synthesised. 15 proteins expressed by breast cancer cells were identified as factors that mediate breast cancer bone metastasis: ICAM-1, cadherin-11, osteoactivin, bone sialoprotein, CCN3, IL-11, CCL2, CITED2, CXCR4, CTGF, OPN, CX3CR1, TWIST1, adrenomedullin and Enpp1. Upregulation or overexpression of one or more of them by breast cancer cells resulted in increased breast cancer metastasis to bone in vivo, except for CCL2 where bone-metastatic cells showed a reduced expression of this factor. All factors identified, here expressed by breast cancer cells, are proteins that are normally expressed in the bone microenvironment and linked to physiologic bone functions. All have a functional role in one of more of the following: cell proliferation and differentiation, bone mineralization and remodelling, cell adhesion and/or chemokine signalling. Six of them (cadherin-11, ICAM-1, OPN, CX3CR1, CCN3 and osteoactivin) have a reported function in cell adhesion and another eight (CCN3, osteoactivin, Enpp1, IL-11, CTGF, TWIST1, adrenomedullin and CITED2) are reported to be involved in cell proliferation and differentiation. This review collates and synthesises published evidence to increase our understanding of the biology of breast cancer osteomimicry in the development of bone metastasis. Findings of this review suggest that changes in expression of proteins in breast cancer cells that confer osteomimicry facilitate homing to bone to enable the development of bone metastasis.

Cao X, Zou H, Cao J, et al.
A candidate Chinese medicine preparation-Fructus Viticis Total Flavonoids inhibits stem-like characteristics of lung cancer stem-like cells.
BMC Complement Altern Med. 2016; 16:364 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer stem cells (CSCs) are considered as the origin of tumor relapse. Here, we investigated the effects of Fructus Viticis total flavonoids (FVTF) on the characteristics of lung cancer stem-like cells (LCSLCs) derived from human small cell lung cancer NCI-H446 cell line and its potential mechanism.
METHODS: Human small cell lung cancer NCI-H446 cell line was cultured in vitro. The CD133(+) cells were sorted from NCI-H446 cell line by magnetic separation. The suspended culture with stem cell-conditioned medium was used to amplify CD133(+) sphere-forming cells (SFCs). The stem cell characteristics of CD133(+) SFCs were evaluated using cell self-renewal capacity by tumor sphere formation assay, migration and invasion capacity by Transwell assay, tumorigenicity by xenograft model in nude mouse and cancer stem cell markers expression levels by western blot. The effects of FVTF on the properties of LCSLCs were examined by tumorsphere formation assay and transwell chamber assay. The expression level of p-Akt was determined by western blot analysis.
RESULT: CD133(+) SFCs derived from human small cell lung cancer NCI-H446 cells exhibited stemness properties of tumorsphere formation and tumorigenesis capacity comparing to the parental cells. FVTF relative selectively inhibited the proliferation of LCSLCs, suppressed tumor sphere forming capacity and migration and invasion of LCSLCs, and down-regulated the protein expression of stem cell markers (CD133, CD44 and ALDH1), self-renewal associated transcription factors (Bmi1, Nanog and OCT4) and invasion associated transcription factors (Twist1 and Snail1) in a dose-dependent manner. Moreover, we found that FVTF treatment could significantly decrease the phosphorylation level of Akt in LCSLCs. Meanwhile, LY294002 and FVTF synergistically inhibited the characteristics of LCSLCs.
CONCLUSION: FVTF inhibits the characteristics of LCSLCs through down-regulating expression of p-Akt.

Sridaran D, Ramamoorthi G, MahaboobKhan R, Kumpati P
Oxystressed tumor microenvironment potentiates epithelial to mesenchymal transition and alters cellular bioenergetics towards cancer progression.
Tumour Biol. 2016; 37(10):13307-13322 [PubMed] Related Publications
During tumorigenesis, cancer cells generate complex, unresolved interactions with the surrounding oxystressed cellular milieu called tumor microenvironment (TM) that favors spread of cancer to other body parts. This dissemination of cancer cells from the primary tumor site is the main clinical challenge in cancer treatment. In addition, the significance of enhanced oxidative stress in TM during cancer progression still remains elusive. Thus, the present study was performed to investigate the molecular and cytoskeletal alterations in breast cancer cells associated with oxystressed TM that potentiates metastasis. Our results showed that depending on the extent of oxidative stress in TM, cancer cells exhibited enhanced migration and survival with reduction of chemosensitivity. Corresponding ultrastructural analysis showed radical cytoskeletal modifications that reorganize cell-cell interactions fostering transition of epithelial cells to mesenchymal morphology (EMT) marking metastasis, which was reversed upon antioxidant treatment. Decreased E-cadherin and increased vimentin, Twist1/2 expression corroborated the initiation of EMT in oxystressed TM-influenced cells. Further evaluation of cellular energetics demonstrated significant metabolic reprogramming with inclination towards glucose or external glutamine from TM as energy source depending on the breast cancer cell type. These observations prove the elemental role of oxystressed TM in cancer progression, initiating EMT and metabolic reprogramming. Further cell-type specific metabolomic analysis would unravel the alternate mechanisms in cancer progression for effective therapeutic intervention. Graphical abstract Schematic representation of the study and proposed mechanism of oxystressed TM influenced cancer progression. Cancer cells exhibit a close association with tumor microenvironment (TM), and oxystressed TM enhances cancer cell migration and survival and reduces chemosensitivity. Oxystressed TM induces dynamic cytomorphological variations, alterations in expression patterns of adhesion markers, redox homeostasis, and metabolic reprogramming that supports epithelial to mesenchymal transition and cancer progression.

Cao X, Ren K, Song Z, et al.
7-Difluoromethoxyl-5,4'-di-n-octyl genistein inhibits the stem-like characteristics of gastric cancer stem-like cells and reverses the phenotype of epithelial-mesenchymal transition in gastric cancer cells.
Oncol Rep. 2016; 36(2):1157-65 [PubMed] Related Publications
7-Difluoromethoxyl-5,4'-di-n-octyl genistein (DFOG), a novel synthetic genistein analogue, exerts anticarcinogenic activity in several types of cancers, including gastric cancer. Accumulating evidence in recent years strongly indicates the existence of cancer stem cells in gastric cancer. The objective of the present study was to investigate whether DFOG inhibits the stemness and reverses the epithelial-mesenchymal transition (EMT) phenotype of gastric cancer stem-like cells (GCSLCs) derived from human gastric cancer SGC-7901 cells and to identify its potential mechanism. Sphere-forming cells (SFCs) from the SGC-7901 cells possessed the properties of GCSLCs. DFOG preferentially inhibited self-renewal, cell migration and cell invasion, and downregulated the expression of stem cell biomarkers in a dose-dependent manner. At the molecular level, these effects were accompanied by the downregulation of forkhead box M1 (FoxM1). Meanwhile, FoxM1 siRNA transfection was able to synergize the inhibition of expression of FoxM1 and Twist1 induced by DFOG in GCSLCs. In addition, we found that DFOG treatment decreased the expression of N-cadherin and increased the expression of E-cadherin. More importantly, FoxM1 siRNA transfection cooperated with DFOG to suppress the self-renewal capacity, cell migration and cell invasion, and downregulated the expression of CD133, CD44, ALDH1, and also regulated the expression of N-cadherin and E-cadherin. These findings showed that DFOG inhibited the stem-like characteristics of GCSLCs and reversed the EMT phenotype by modulation of FoxM1 and further decreased Twist1 expression. Our results provide a further rationale and experimental basis for using DFOG to improve the efficacy of treatment for patients with gastric cancer.

Lin X, Sun B, Zhu D, et al.
Notch4+ cancer stem-like cells promote the metastatic and invasive ability of melanoma.
Cancer Sci. 2016; 107(8):1079-91 [PubMed] Free Access to Full Article Related Publications
Sphere formation in conditioned serum-free culture medium supplemented with epidermal growth factor and basic fibroblast growth factor (tumorospheres) is considered useful for the enrichment of cancer stem-like cells, also known as tumor-initiating cells. We used a gene expression microarray to investigate the gene expression profile of melanoma cancer stem-like cells (MCSLCs). The results showed that MCSLCs highly expressed the following Notch signaling pathway molecules: Notch3 (NM_008716), Notch4 (NM_010929), Dtx4 (NM_172442), and JAG2 (NM_010588). Immunofluorescence staining showed tumorosphere cells highly expressed Notch4. Notch4(high) B16F10 cells were isolated by FACS, and Western blotting showed that high Notch4 expression is related to the expression of epithelial-mesenchymal transition (EMT)-associated proteins. Reduced invasive and migratory properties concomitant with the downregulation of the EMT markers Twist1, vimentin, and VE-cadherin and the overexpression of E-cadherin was observed in human melanoma A375 and MUM-2B cells. In these cells, Notch4 was also downregulated, both by Notch4 gene knockdown and by application of the γ-secretase inhibitor, DAPT. Mechanistically, the re-overexpression of Twist1 by the transfection of cells with a Twist1 expression plasmid led to an increase in VE-cadherin expression and a decrease in E-cadherin expression. Immunohistochemical analysis of 120 human melanoma tissues revealed a significant correlation between the high expression of Notch4 and the metastasis of melanoma. Taken together, our findings indicate that Notch4+ MCSLCs trigger EMT and promote the metastasis of melanoma cells.

Sugimoto M, Kohashi K, Itsumi M, et al.
Epithelial to Mesenchymal Transition in Clear Cell Renal Cell Carcinoma with Rhabdoid Features.
Pathobiology. 2016; 83(6):277-86 [PubMed] Related Publications
AIMS: The aims of this study were to investigate the association of renal cell carcinoma (RCC) displaying rhabdoid features and morphologically mesenchymal characteristics with epithelial to mesenchymal transition (EMT), and to clarify the expression of EMT markers.
METHODS: We investigated the expression of EMT markers (E-cadherin, vimentin, Snail, Slug, ZEB1, ZEB2 and Twist1) using immunohistochemistry, Western blotting and real-time polymerase chain reaction in 18 cases of clear cell RCC (ccRCC) with rhabdoid features and 74 ccRCC cases with Fuhrman grade 1-3 (G1 to G3).
RESULTS: In ccRCCs with rhabdoid features, low E-cadherin and high vimentin expression were found. In G1 to G3 ccRCCs, low E-cadherin expression and high expression of vimentin, ZEB1 and ZEB2 were found. There was no significant difference in the immunoexpression of E-cadherin and vimentin between the two ccRCC groups.
CONCLUSIONS: The rhabdoid features may histologically and biologically be associated with EMT in ccRCC. There is a possibility that in G1 to G3 ccRCCs showing epithelial structures, other cell-cell adhesion mechanisms apart from E-cadherin adhesion may continue to work, and that ccRCC with rhabdoid features may be caused by an inactivation or loss of these mechanisms.

Gallardo M, Calaf GM
Curcumin and epithelial-mesenchymal transition in breast cancer cells transformed by low doses of radiation and estrogen.
Int J Oncol. 2016; 48(6):2534-42 [PubMed] Related Publications
Breast cancer is a major cause of global mortality in women. Curcumin exerts anti-proliferative, anti-migratory and apoptotic effects. The aim of this study was to evaluate gene expression involved in epithelial-mesenchymal transition (EMT). An in vitro model was developed with the MCF-10F immortalized breast epithelial cell line exposed to low radiation doses of high LET (linear energy transfer) α-particles (150 keV/µm) and cultured in the presence of 17β-estradiol (estrogen). The following cell lines were used: i) MCF-10F, normal; ii) Alpha5, pre-tumorigenic, and iii) Tumor2 derived from Alpha5 injected into the nude mice. Our previous results have shown that Alpha5 and Tumor2 increased cell proliferation, anchorage independency, invasive capabilities and tumor formation in nude mice in comparison to control. Results indicated that curcumin decreased expression of EMT-related genes in Tumor2 cell line when compared to its counterpart as E-cadherin, N-cadherin, ZEB2, Twist1, Slug, Axl, vimentin, STAT-3, fibronectin; and genes p53 and caveolin-1, as well as apoptotic genes caspase-3, caspase-8, and others such as cyclin D1 and NFκB. All these changes induced a decrease in migratory and invasive capabilities of such a cell line. Thus, it seems that curcumin may impinge upon apoptosis and metastatic properties of the malignant cells exerting antitumor activity in breast cancer cells transformed by low doses of α-particles and estrogen in vitro.

Zhao Y, Jin X, Li N, et al.
[Expression and Clinical Significance of ALDH1 and Twist in Gastric Adenocarcinoma].
Sichuan Da Xue Xue Bao Yi Xue Ban. 2016; 47(1):54-9 [PubMed] Related Publications
OBJECTIVE: To investigate the expressions and clinical significances of aldehyde dehydrogenase 1 (ALDH1) and Twist in gastric adenocarcinoma.
METHODS: A total of 86 cases of gastric adenocarcinoma was included in this study. GAC specimens and normal gastric tissues were obtained from the patients. In situ hybridization method was used to detect the expression of ALDH1, Twist mRNA. Immuohistochemistry was used to detect the expression of ALDH1, Twist, E-cadherin and N-cadherin. The relationship of ALDH1 and Twist with epithelial-mesenchymal transition phenomenon was studied. Survival analysis was carried to demonstrate the relationships of clinical pathological parameters with 5-year survival rate.
RESULTS: The positive rates of ALDH1, Twist mRNA in GAC tissues were 57.0% and 53.5%, while the positive rates of proteins were 60.5% and 58.1%, which were significantly higher than those in normal controls (P < 0.05). The expression of ALDH1 protein was significantly correlated with TNM stage and lymph node metastasis (P < 0.05). The expression of Twist protein was significantly correlated with distant metastasis, lymph node metastasis and invasion depth (P < 0.05). The expressions of ALDH1 and Twist were significantly correlated with low expression of E-cadherin and high expression of N-cadherin (P < 0.05). Univartate analysis showed TNM stage, lymph node metastasis, distant metastasis and tumor size, the expression of ALDH1 and Twist related to 5-year survival rate (P < 0.05).
CONCLUSION: The enhanced expression of ALDH1 and Twist in gastric adenocarcinoma may play a role in GAC invasion, metastasis and prognosis.

Tanabe A, Tanikawa K, Tsunetomi M, et al.
RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated.
Cancer Lett. 2016; 376(1):34-42 [PubMed] Related Publications
YTH domain containing 2 (YTHDC2) is a member of the DExD/H-box family of ATP-dependent RNA helicases. We previously found that YTHDC2 expression is up-regulated in several human cancer cells. In this study, we demonstrate novel roles for YTHDC2 in metastasis of colon tumor cells via translation-dependent pathway. Knockdown of YTHDC2 attenuated protein expression of metastasis-related genes, such as hypoxia-inducible factor-1alpha (HIF-1α), and inhibited metastasis of colon tumor cells in vitro and in vivo. To confirm that YTHDC2 promotes translation initiation by unwinding the 5'-untranslated region (5'UTR) of mRNA, we constructed a firefly luciferase reporter containing the 5'UTR of the HIF-1α mRNA and showed reduction in luciferase activity in YTHDC2-silenced cells. Furthermore, we examined expression levels of YTHDC2 by immunohistochemical staining in human colon cancer tissues from 72 patients and found a significantly positive correlation between YTHDC2 expression and the tumor stage, including metastasis. In conclusion, these results suggest that the RNA helicase YTHDC2 contributes to colon tumor metastasis by promoting translation of HIF-1α and that YTHDC2 is potentially a diagnostic marker and target gene for treating colon cancer patients.

Lee HJ, Hanibuchi M, Kim SJ, et al.
Treatment of experimental human breast cancer and lung cancer brain metastases in mice by macitentan, a dual antagonist of endothelin receptors, combined with paclitaxel.
Neuro Oncol. 2016; 18(4):486-96 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: We recently demonstrated that brain endothelial cells and astrocytes protect cancer cells from chemotherapy through an endothelin-dependent signaling mechanism. Here, we evaluated the efficacy of macitentan, a dual endothelin receptor (ETAR and ETBR) antagonist, in the treatment of experimental breast and lung cancer brain metastases.
METHODS: The effect of macitentan on astrocyte- and brain endothelial cell-mediated chemoprotective properties was measured in cytotoxic assays. We compared survival of mice bearing established MDA-MB-231 breast cancer or PC-14 non-small cell lung cancer (NSCLC) brain metastases that were treated with vehicle, macitentan, paclitaxel, or macitentan plus paclitaxel. Cell division, apoptosis, tumor vasculature, and expression of survival-related proteins were assessed by immunofluorescent microscopy.
RESULTS: Cancer cells and tumor-associated endothelial cells expressed activated forms of AKT and MAPK in vehicle- and paclitaxel-treated groups in both metastasis models, but these proteins were downregulated in metastases of mice that received macitentan. The survival-related proteins Bcl2L1, Gsta5, and Twist1 that localized to cancer cells and tumor-associated endothelial cells in vehicle- and paclitaxel-treated tumors were suppressed by macitentan. Macitentan or paclitaxel alone had no effect on survival. However, when macitentan was combined with paclitaxel, we noted a significant reduction in cancer cell division and marked apoptosis of both cancer cells and tumor-associated endothelial cells. Moreover, macitentan plus paclitaxel therapy significantly increased overall survival by producing complete responses in 35 of 35 mice harboring brain metastases.
CONCLUSIONS: Dual antagonism of ETAR and ETBR signaling sensitizes experimental brain metastases to paclitaxel and may represent a new therapeutic option for patients with brain metastases.

Kwon YJ, Baek HS, Ye DJ, et al.
CYP1B1 Enhances Cell Proliferation and Metastasis through Induction of EMT and Activation of Wnt/β-Catenin Signaling via Sp1 Upregulation.
PLoS One. 2016; 11(3):e0151598 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Cytochrome P450 1B1 (CYP1B1) is a major E2 hydroxylase involved in the metabolism of potential carcinogens. CYP1B1 expression has been reported to be higher in tumors compared to normal tissues, especially in hormone-related cancers including breast, ovary, and prostate tumors. To explore the role of CYP1B1 in cancer progression, we investigated the action of CYP1B1 in cells with increased CYP1B1 via the inducer 7,12-dimethylbenz[α]anthracene (DMBA) or an overexpression vector, in addition to decreased CYP1B1 via the inhibitor tetramethoxystilbene (TMS) or siRNA knockdown. We observed that CYP1B1 promoted cell proliferation, migration, and invasion in MCF-7 and MCF-10A cells. To understand its molecular mechanism, we measured key oncogenic proteins including β-catenin, c-Myc, ZEB2, and matrix metalloproteinases following CYP1B1 modulation. CYP1B1 induced epithelial-mesenchymal transition (EMT) and activated Wnt/β-catenin signaling via upregulation of CTNNB1, ZEB2, SNAI1, and TWIST1. Sp1, a transcription factor involved in cell growth and metastasis, was positively regulated by CYP1B1, and suppression of Sp1 expression by siRNA or DNA binding activity using mithramycin A blocked oncogenic transformation by CYP1B1. Therefore, we suggest that Sp1 acts as a key mediator for CYP1B1 action. Treatment with 4-hydroxyestradiol (4-OHE2), a major metabolite generated by CYP1B1, showed similar effects as CYP1B1 overexpression, indicating that CYP1B1 activity mediated various oncogenic events in cells. In conclusion, our data suggests that CYP1B1 promotes cell proliferation and metastasis by inducing EMT and Wnt/β-catenin signaling via Sp1 induction.

Zhao N, Sun H, Sun B, et al.
miR-27a-3p suppresses tumor metastasis and VM by down-regulating VE-cadherin expression and inhibiting EMT: an essential role for Twist-1 in HCC.
Sci Rep. 2016; 6:23091 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: Twist-1 and miRNAs have been reported to be associated with tumor metastasis and angiogenesis. However, the relationship between Twist-1 and miRNAs and the function of miRNAs remain largely undefined. We aimed to reveal the Twist-1-related miRNA expression profile and to determine whether Twist-1 functions in tumor metastasis and vasculogenic mimicry (VM) by regulating miRNA expression in hepatocellular carcinoma (HCC). Results showed that the expression of miR-27a-3p was consistently down-regulated in HCC cell lines and tissue samples displaying high expression of Twist-1. Both loss- and gain-of-function assays revealed suppressive effects of miR-27a-3p. Low miR-27a-3p expression was significantly associated with early metastasis in HCC. Subsequent investigations revealed that miR-27a-3p mediated the inhibition of epithelial-mesenchymal transition (EMT). Additional experiments showed that VE-cadherin is a direct target of miR-27a-3p and further demonstrated the critical role of miR-27a-3p in suppressing tumor metastasis and VM.
CONCLUSIONS: Twist-1 up-regulation in HepG2 cells resulted in the differential expression of 18 miRNAs. Among them, miR-27a-3p deregulation contributed to VM and metastasis. The miR-27a-3p-mediated down-regulation of VE-cadherin and inhibition of EMT may be essential for Twist-1 to induce tumor metastasis and VM. Our findings highlight the importance of miR-27a-3p and suggest a promising new strategy for anti-HCC therapy.

Sun T, Fu J, Shen T, et al.
The Small C-terminal Domain Phosphatase 1 Inhibits Cancer Cell Migration and Invasion by Dephosphorylating Ser(P)68-Twist1 to Accelerate Twist1 Protein Degradation.
J Biol Chem. 2016; 291(22):11518-28 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
Twist1 is a basic helix-loop-helix transcription factor that strongly promotes epithelial-to-mesenchymal transition, migration, invasion, and metastasis of cancer cells. The MAPK-phosphorylated Twist1 on its serine 68 (Ser(P)(68)-Twist1) has a significantly enhanced stability and function to drive cancer cell invasion and metastasis. However, the phosphatase that dephosphorylates Ser(P)(68)-Twist1 and destabilizes Twist1 has not been identified and characterized. In this study, we screened a serine/threonine phosphatase cDNA expression library in HEK293T cells with ectopically coexpressed Twist1. We found that the small C-terminal domain phosphatase 1 (SCP1) specifically dephosphorylates Ser(P)(68)-Twist1 in both cell-free reactions and living cells. SCP1 uses its amino acid residues 43-63 to interact with the N terminus of Twist1. Increased SCP1 expression in cells decreased Ser(P)(68)-Twist1 and total Twist1 proteins, whereas knockdown of SCP1 increased Ser(P)(68)-Twist1 and total Twist1 proteins. Furthermore, the levels of SCP1 are negatively correlated with Twist1 protein levels in several cancer cell lines. SCP1-dephosphorylated Twist1 undergoes fast degradation via the ubiquitin-proteasome pathway. Importantly, an increase in SCP1 expression in breast cancer cells with either endogenous or ectopically expressed Twist1 largely inhibits the Twist1-induced epithelial-to-mesenchymal transition phenotype and the migration and invasion capabilities of these cells. These results indicate that SCP1 is the phosphatase that counterregulates the MAPK-mediated phosphorylation of Ser(68)-Twist1. Thus, an increase in SCP1 expression and activity may be a useful strategy for eliminating the detrimental roles of Twist1 in cancer cells.

Nicolay JP, Felcht M, Schledzewski K, et al.
Sézary syndrome: old enigmas, new targets.
J Dtsch Dermatol Ges. 2016; 14(3):256-64 [PubMed] Related Publications
Sézary syndrome, the leukemic variant of cutaneous T-cell lymphoma, is still an enigmatic disease with a fatal prognosis. Recent research, however, has identified a multitude of dysregulated molecular pathways that contribute to malignant transformation and therapy resistance of Sézary cells (SC). With respect to T-cell development, SC either represent naive T cells, T effector memory or T central memory cells. Functionally, SC may differentiate into Th2, Treg, or even Th17 cells. Despite their plasticity, SC express characteristic diagnostic marker proteins including CD158k, CD164, FcRL3, and PD-1 as well as skin-homing receptors such as CLA and CCR4. Already tested in (pre)clinical trials, CD158k, PD-1, CTLA-4, and CCR4 also represent promising therapeutic targets. Molecular alterations in SC include transcription factors such as STAT3, 4, and 5, as well as TWIST1 and TOX. TWIST1 induces expression of DNM3os containing the miR-199a2/214 cluster, a key hub controlling multiple cancer networks. In addition, activation of NFκB and the MAPK pathway as well as altered TCR signaling cause apoptosis resistance. Recently, whole genome and exome sequencing has revealed somatic copy number variations as predominant mutations in SC, primarily affecting apoptosis, NFκB signaling, DNA integrity, and T-cell activation. In order to facilitate development of novel therapies, improved in vivo models, which better reflect the pathogenesis and clinical course of Sézary syndrome, are currently being generated.

McCullough LE, Chen J, Cho YH, et al.
DNA methylation modifies the association between obesity and survival after breast cancer diagnosis.
Breast Cancer Res Treat. 2016; 156(1):183-94 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
Mechanisms underlying the poor breast cancer prognosis among obese women are unresolved. DNA methylation levels are linked to obesity and to breast cancer survival. We hypothesized that obesity may work in conjunction with the epigenome to alter prognosis. Using a population-based sample of women diagnosed with first primary breast cancer, we examined modification of the obesity-mortality association by DNA methylation. In-person interviews were conducted approximately 3 months after diagnosis. Weight and height were assessed [to estimate body mass index (BMI)], and blood samples collected. Promoter methylation of 13 breast cancer-related genes was assessed in archived tumor by methylation-specific PCR and Methyl Light. Global methylation in white blood cell DNA was assessed by analysis of long interspersed elements-1 (LINE-1) and with the luminometric methylation assay (LUMA). Vital status among 1308 patients (with any methylation biomarker and complete BMI assessment) was determined after approximately 15 years of follow-up (N = 194/441 deaths due to breast cancer-specific/all-cause mortality). We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) using two-sided p values of 0.05. Breast cancer-specific mortality was higher among obese (BMI ≥ 30) patients with promoter methylation in APC (HR = 2.47; 95 % CI = 1.43-4.27) and TWIST1 (HR = 4.25; 95 % CI = 1.43-12.70) in breast cancer tissue. Estimates were similar, but less pronounced, for all-cause mortality. Increased all-cause (HR = 1.81; 95 % CI = 1.19-2.74) and breast cancer-specific (HR = 2.61; 95 % CI = 1.45-4.69) mortality was observed among obese patients with the lowest LUMA levels. The poor breast cancer prognosis associated with obesity may depend on methylation profiles, which warrants further investigation.

Liu H, Wang H, Liu X, Yu T
miR-1271 inhibits migration, invasion and epithelial-mesenchymal transition by targeting ZEB1 and TWIST1 in pancreatic cancer cells.
Biochem Biophys Res Commun. 2016; 472(2):346-52 [PubMed] Related Publications
Pancreatic cancer (PC) remains one of the most lethal types of cancer in adults. The purpose of this study was to determine the role of miR-1271 in regulation of epithelial mesenchymal transition (EMT) and metastasis of pancreatic cancer cells. miR-1271 was identified to be significantly down-regulated in PC tissues by miRNA array. Also, an increase of EMT-regulators ZEB1 and TWIST1 expression level is accompanied by a decrease of miR-1271. We showed that expression of miR-1271 was significantly down-regulated in PC tissues as compared with that in normal tissues. In addition, our results showed that miR-1271 expression levels were decreased while ZEB1 and TWIST1 expression levels were increased in detected PC cell lines. Moreover, ectopic expression of miR-1271 suppressed and antagomiR-1271 promoted proliferation, migration, and invasion in SW1990 and PANC-1 cells. Bioinformatics coupled with luciferase and Western blot assays also revealed that miR-1271 inhibited expression of ZEB1 and TWIST1, which are master regulators of tumor metastasis. Our study first indicates that miR-1271 functions as a suppressor in regulating of pancreatic cancer EMT by targeting ZEB1 and TWIST1, and it promise as a therapeutic target and prognostic marker for metastatic pancreatic cancer.

Iwahashi S, Shimada M, Utsunomiya T, et al.
Epithelial-mesenchymal transition-related genes are linked to aggressive local recurrence of hepatocellular carcinoma after radiofrequency ablation.
Cancer Lett. 2016; 375(1):47-50 [PubMed] Related Publications
We reported that poor prognoses of hepatocellular carcinoma (HCC) patients after radiofrequency ablation (RFA) are owing to up-regulation of expression of hypoxia-inducible factor-1 and epithelial cell adhesion molecule. We investigated aggressive progression in residual liver tumors (RLTs) after RFA to focus on expression of epithelial-mesenchymal transition (EMT)-related genes and miRNAs. Ten patients with recurrent HCC post-RFA who underwent hepatectomy (RFA group) and 78 patients with HCC without prior RFA (non-RFA group) were enrolled. We examined expression of transforming growth factor (TGF)-β, Twist, vimentin, and Snail-1 mRNAs in tumor tissues, and expression of miR-34a and miR-200c. Expression of TGF-β, Twist and Snail-1 in the RFA group was significantly higher than that in the non-RFA group (P < 0.05); vimentin expression in the RFA group was higher than that in the non-RFA group (P = 0.07). Expression of miR-200c and miR-34a in the RFA group was significantly lower than that in the non-RFA group (miR-200c: P = 0.04; miR-34a: P < 0.01). Increased expression of EMT markers through down-regulation of miRNA expression in RLTs after RFA may be related to poor prognoses of HCC patients with aggressive local recurrence after RFA.

Cao HH, Chu JH, Kwan HY, et al.
Inhibition of the STAT3 signaling pathway contributes to apigenin-mediated anti-metastatic effect in melanoma.
Sci Rep. 2016; 6:21731 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
Signal transducer and activator of transcription 3 (STAT3) signaling is constantly activated in human melanoma, and promotes melanoma metastasis. The dietary flavonoid apigenin is a bioactive compound that possesses low toxicity and exerts anti-metastatic activity in melanoma. However, the anti-metastasis mechanism of apigenin has not been fully elucidated. In the present study, we showed that apigenin suppressed murine melanoma B16F10 cell lung metastasis in mice, and inhibited cell migration and invasion in human and murine melanoma cells. Further study indicated that apigenin effectively suppressed STAT3 phosphorylation, decreased STAT3 nuclear localization and inhibited STAT3 transcriptional activity. Apigenin also down-regulated STAT3 target genes MMP-2, MMP-9, VEGF and Twist1, which are involved in cell migration and invasion. More importantly, overexpression of STAT3 or Twist1 partially reversed apigenin-impaired cell migration and invasion. Our data not only reveal a novel anti-metastasis mechanism of apigenin but also support the notion that STAT3 is an attractive and promising target for melanoma treatment.

Guo W, You X, Xu D, et al.
PAQR3 enhances Twist1 degradation to suppress epithelial-mesenchymal transition and metastasis of gastric cancer cells.
Carcinogenesis. 2016; 37(4):397-407 [PubMed] Related Publications
Twist1 is an essential transcription factor required to initiate epithelial-mesenchymal transition (EMT) and promote tumor metastasis. PAQR3 is a newly found tumor suppressor that is frequently downregulated in many types of human cancers. Downregulation of PAQR3 is associated with accelerated metastasis and poor prognosis of the patients with gastric cancers. In this study, we demonstrate that PAQR3 is actively involved in the degradation of Twist1 and whereby regulates EMT and metastasis of gastric cancer cells. PAQR3 overexpression reduces the protein level but not the mRNA level of Twist1. The protein stability and polyubiquitination of Twist1 are altered by PAQR3. PAQR3 forms a complex with Twist1 and BTRC, an E3 ubiquitin ligase. PAQR3 enhances the interaction between Twist1 and BTRC. Twist1 is mobilized from the nucleus to a proteasome-containing structure in the cytoplasm upon overexpression of PAQR3 and BTRC, which is required for PAQR3-induced degradation of Twist1. The Twist1 box domain of the Twist1 protein is required for the interaction of Twist1 with both PAQR3 and BTRC, indispensable for PAQR3-mediated degradation of Twist1. Both BTRC and Twist1 are required for the inhibitory effects of PAQR3 on migration and EMT phenotype of gastric cancers cells. Importantly, Twist1 is indispensable for the inhibitory effect of PAQR3 on metastasis of gastric cancer cells in vivo Collectively, these findings not only pinpoint that Twist1 mediates the modulatory function of PAQR3 on EMT and metastasis but also suggest that targeting Twist1 is a promising strategy to control metastasis of tumors with downregulation of PAQR3.

Mego M, Cholujova D, Minarik G, et al.
CXCR4-SDF-1 interaction potentially mediates trafficking of circulating tumor cells in primary breast cancer.
BMC Cancer. 2016; 16:127 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
BACKGROUND: Cytokines are involved in cancer invasion and metastasis. Circulating tumor cells (CTCs) play key role in tumor dissemination and are an independent survival predictor in breast cancer patients. The aim of this study was to assess correlation between CTCs and plasma cytokines in primary breast cancer (PBC) patients.
METHODS: This study included 147 chemotherapy naïve PBC patients. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoetic cells using RossetteSep™ negative selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (Twist1, Snail1, Slug, Zeb1) and epithelial (Ck19) gene transcripts by qRT-PCR. The concentrations of 51 plasma cytokines were measured using multiplex bead arrays.
RESULTS: CTCs were detected in 25.2% patients. CTCs exhibiting only epithelial markers (CTC_EP) and only EMT markers (CTC_EMT) were present evenly in 11.6% patients, while CTCs co-expressing both markers were detected in 2.0% patients. Patients with presence of CTC_EP in peripheral blood had significantly elevated levels of plasma IFN-α2, IL-3, MCP-3, β-NGF, SCF, SCGF-β, TNF-β and SDF-1 compared to patients without CTC_EP. CTC_EP exhibited overexpression of SDF-1 receptor and CXCR4, but not other corresponding cytokine receptor, and in multivariate analysis SDF-1 was independently associated with CTC_EP. There was an inverse correlation between CTC_EMT and plasma cytokines CTACK, β-NGF and TRAIL, while presence of either subtype of CTCs was associated with increased level of TGF-β2.
CONCLUSION: Using cytokine profiling, we identified cytokines associated with CTCs subpopulations in peripheral blood of PBC. Our data suggest that CXCR4-SDF-1 axis is involved in mobilization and trafficking of epithelial CTCs.

Khanbabaei H, Teimoori A, Mohammadi M
The interplay between microRNAs and Twist1 transcription factor: a systematic review.
Tumour Biol. 2016; 37(6):7007-19 [PubMed] Related Publications
Twist1 (also known as Twist) is a transcription factor that belongs to the family of basic helix-loop-helix (bHLH) proteins. It functions as a negative regulator of epithelial gene expression and a positive regulator of mesenchymal gene expression, thereby leading to induction of the epithelial mesenchymal transition (EMT), a process in which epithelial cells acquire the motile and migratory characteristics of mesenchymal cells. In addition to regulating the expression of protein-coding genes, Twist1 regulates the expression of microRNAs (miRNAs), adding a regulatory layer to EMT induction. Interestingly, the mRNA of Twist1 represents a downstream target of miRNAs, indicating an intricate network between miRNAs and Twist1. This network was shown to play multiple roles in cancer cell migration, invasion, and metastasis. The network can induce angiogenesis, protect cells from oncogene-induced apoptosis and senescence, enhance cancer cell resistance to conventional therapies, and increase cancer stem cell (CSC) populations. Recently, miRNAs have attracted considerable attention as potential promising tools in cancer therapies. Thus, this systematic review was conducted to clarify the reciprocal link between Twist1 and miRNAs in order to provide potential candidate miRNAs for diagnostic and therapeutic approaches in cancer treatment.

Zhang J, Zhu L, Fang J, et al.
LRG1 modulates epithelial-mesenchymal transition and angiogenesis in colorectal cancer via HIF-1α activation.
J Exp Clin Cancer Res. 2016; 35:29 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
BACKGROUND: Leucine-rich-alpha-2-glycoprotein 1 (LRG1) has been reported to be involved in several tumors, whether it participates in colorectal cancer (CRC) progression remains unclear. Here, we investigated the biological function and underlying molecular mechanisms of LRG1 in CRC.
METHODS: The mRNA and protein levels of LRG1 were assessed in CRC tissues through RT-PCR and immunohistochemistry, respectively. HCT116 and SW480 cells were treated with LRG1 siRNA, control siRNA, or recombinant LRG1. Transwell invasion assays and wound healing assays were performed to evaluate the invasion and migration of CRC cells. Epithelial-to-mesenchymal transition (EMT) markers of E-cadherin, VDR, N-cadherin, α-SMA, Vimentin and Twist1 were detected by RT-PCR and western blot. Enzyme-linked immunosorbent assay was used to measure the secretion level of VEGF-A. Conditioned medium from CRC cells was collected for endothelial cell migration, tube formation and aortic ring sprouting assays.
RESULTS: LRG1 was overexpressed in CRC tissues and associated with cancer aggressiveness. LRG1 was further found to induce the EMT process, as well as CRC cell migration and invasion capacity. In addition, LRG1 promoted VEGF-A expression in CRC cells and contributed to tumor angiogenesis. Furthermore, HIF-1α could be induced by LRG1 in a concentration- and time-dependent manner, which was responsible for LRG1-induced VEGF-A expression and EMT.
CONCLUSIONS: The present study suggests that LRG1 plays a crucial role in the progression of CRC by regulating HIF-1α expression, thereby may be a promising therapeutic target of CRC.

Garner JM, Herr MJ, Hodges KB, Jennings LK
The utility of tetraspanin CD9 as a biomarker for metastatic clear cell renal cell carcinoma.
Biochem Biophys Res Commun. 2016; 471(1):21-5 [PubMed] Related Publications
The use of tetraspanin CD9 as a biomarker for renal cell carcinomas (RCC) has been explored with minor conclusions. Identification of a biomarker that not only distinguishes between the different types of renal cell carcinomas, but also predicts the metastatic potential of these tumors would significantly advance diagnosis and prognosis of kidney cancers. We utilized established cell lines to better understand the contribution of CD9 to the metastatic potential of clear cell renal cell carcinomas, and then applied our findings to the TCGA database and immunohistochemical analysis of human samples based on tumor grading to determine the utility of CD9 as a biomarker for RCC. Clear cell renal cell carcinoma (ccRCC) cell expression of tetraspanin CD9 was compared to normal kidney cells and found to be elevated. Upon knockdown of CD9, ccRCC cells obtained a more metastatic phenotype. We found E-cadherin expression to be repressed and the endothelial to mesenchymal transition markers Snail, Twist1, and Zeb1 to be elevated upon CD9 knockdown. Upon observing these gene expression changes in the TCGA database and in 10 cases, we found that CD9 and E-cadherin expression was lowered in higher grade ccRCC tumors. There was a significant correlation between CD9 and either E-cadherin, Snail, or Zeb1 in these tumors. Collectively, using tetraspanin CD9 in tandem with E-cadherin as a biomarker in renal cell carcinoma will help to not only distinguish between types, but also predict the metastatic potential of RCC.

Cheng HL, Lin CW, Yang JS, et al.
Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cells metastasis by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways.
Oncotarget. 2016; 7(9):9742-58 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
Zoledronate is a standard treatment for preventing skeletal complications of osteoporosis and some types of cancer associated with bone metastases, but we little know whether the effect of zoledronate on metastasis of osteosarcoma. Here, we investigated the inhibitory effects of zoledronate on cell viability, motility, migration and invasion of 4 osteosarcoma cell lines (Saos2, MG-63, HOS and U2OS) by affecting cell morphology, epithelial-mesenchymal transition (EMT) and cytoskeletal organization as well as induction of E-cadherin and reduction of N-cadherin with activation of transcription factors Slug and Twist, especially in U2OS cells. Zoledronate decreased JNK and p38 phosphorylation and upper streams of focal adhesion kinase (FAK) and Src to suppress the motility, invasiveness and migration of U2OS cells. In addition to zoledronate-inhibited Rho A and Cdc42 membrane translocation and GTPγS activities, the anti-metastatic effects in U2OS cells including inhibition of adhesion were reversed by geranylgeraniol, but not farnesol. In conclusion, Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cell-matrix and cell-cell interactions, migration potential, the invasive activity, and the adhesive ability by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways.

Yang J, Zhang X, Zhang Y, et al.
HIF-2α promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer.
J Exp Clin Cancer Res. 2016; 35:26 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
BACKGROUND: Epithelial-mesenchymal transition (EMT) is a dedifferentiation process that mainly involves in mesenchymal marker upregulation, epithelial maker downregulation and cell polarity loss. Related hypoxia factors play a crucial role in EMT, however, it remains few evidence to clarify the role of HIF-2α in EMT in pancreatic cancer.
METHOD: In this study, we investigated the expression of HIF-2α and E-cadherin by immunohistochemistry in 70 pancreatic cancer patients, as well as the correlation to the clinicopathologic characteristics. Then we regulated the expression of HIF-2α in pancreatic cancer cells to examine the role of HIF-2α on invasion and migration in vitro. Finally, we tested the relation of HIF-2α and EMT related proteins by Western blot and determined whether HIF-2α regulated EMT through Twist regulating the expression of E-cadherin by Chromatin immunoprecipitation (ChIP) assay.
RESULTS: We found that HIF-2α protein was expressed positively in 67.1% (47/70) of pancreatic cancer tissues and 11.4% (8/70) of adjacent non-tumor pancreatic tissues, and there was a significant difference in the positive rate of HIF-2α protein between two groups (χ2 = 45.549, P < 0.05). In addition, the staining for HIF-2α was correlated with tumor differentiation (P < 0.05), clinical stage (P < 0.05) and lymph node metastasis (P < 0.05), while E-cadherin expression was only correlated with lymph node metastasis (P < 0.05). HIF-2α promoted cell migration, invasion in vitro, and regulated the expression of E-cadherin and MMPs, which are critical to EMT. Our further ChIP assay suggested that only Twist2 could bind to the promoter of E-cadherin in -714 bp region site, but there is no positive binding capacity in -295 bp promoter region site of E-cadherin. Clinical tissues IHC staining showed that Twist2 and E-cadherin expression had an obviously negative correlation in pancreatic cancer. Nevertheless, it had no obvious correlation between Twist1 and E-cadherin.
CONCLUSION: These findings indicated that HIF-2α promotes EMT in pancreatic cancer by regulating Twist2 binding to the promoter of E-cadherin, which meant that HIF-2α and this pathway may be effective therapeutic targets for pancreatic cancer.

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