Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: STARD13 (cancer-related)
Background: This study aims to investigate the effects of inhibiting microRNA-9-5p (miR-9-5p) on the expression of StAR-related lipid transfer domain containing 13 (StarD13) and the progress of prostate cancer.
Methods: The mRNA expression levels of miR-9-5p and StarD13 were determined in several prostate cancer cell lines. We chose DU145 and PC-3 cells for further research. The CCK8 assay was used to measure the cell viability. The cell invasion and wound-healing assays were respectively applied to evaluate invasion and migration. The expression of E-cadherin (E-cad), N-cadherin (N-cad) and vimentin were measured via western blot. DU145 and PC-3 cells overexpressing StarD13 were generated to investigate the variation in proliferation, invasion and migration. A luciferase reporter assay was used to identify the target of miR-9-5p.
Results: Our results show that miR-9-5p was highly expressed and StarD13 was suppressed in prostate cancer cells. MiR-9-5p inhibition repressed the cells' viability, invasion and migration. It also increased the expression of E-cad and decreased that of N-cad and vimentin. StarD13 overexpression gave the same results as silencing of miR-9-5p: suppression of cell proliferation, invasion and migration. The bioinformatics analysis predicted StarD13 as a target gene of miR-9-5p. Quantitative RT-PCR, western blot analysis and the dual-luciferase reporter assay were employed to confirm the prediction.
Conclusion: Our results show that miR-9-5p plays a powerful role in the growth, invasion, migration and epithelial-mesenchymal transition (EMT) of prostate cancer cells by regulating StarD13. A therapeutic agent inhibiting miR-9-5p could act as a tumor suppressor for prostate cancer.
Deleted in Liver Cancer (DLC) proteins belong to the family of RhoGAPs and are believed to operate as negative regulators of the Rho family of small GTPases. So far, the role of the first identified member from the DLC family, DLC1, was established as a tumor suppressor in hepatocellular carcinoma. The function of its close family relative, DLC2 is unequivocal. In the present study we attempted to determine whether the loss of DLC2 is a common feature of hepatocellular carcinoma tissue. We examined two types of hepatocellular carcinoma- typical and fibrolamellar one. Our analysis revealed that DLC2 protein is not diminished in cancer tissue when compared to non-cancerous liver specimens. What is more, we observed DLC2 to be more abundantly expressed in cancer tissue, particularly in tumors with the inflammation background. In addition, we found that DLC2 gene status was diploid in virtually all tumor samples examined. Our results indicate that DLC2 is not diminished in hepatocellular carcinoma cells. It appears that members of the DLC family, although structurally highly related, may function differently in cancer cells.
Hu R, Zhu X, Chen C, et al.RNA-binding protein PUM2 suppresses osteosarcoma progression via partly and competitively binding to STARD13 3'UTR with miRNAs.
Cell Prolif. 2018; 51(6):e12508 [PubMed
] Related Publications
OBJECTIVES: This work aims to reveal the roles and related mechanisms of RNA binding protein PUM2 in osteosarcoma progression.
MATERIALS AND METHODS: Transcriptome analysis based on RNA sequencing data, real-time quantitative PCR (RT-qPCR), and western blot analysis were used to detect the expression of RBPs and miRNAs in OS and normal adjacent tissues, and the correlation between them in OS tissues. RT-qPCR, western blot, cell viability, transwell migration, tumour spheres formation and in vivo tumour formation assays were used to examine the effects of RBP PUM2 on OS progression. Additionally, RNA immunoprecipitation (RIP) assay combined with RNA sequencing was performed to determine the binding site of RBP PUM2 on STARD13 3'UTR. Luciferase reporter and RIP assays were used to confirm the binding of miRNAs or PUM2 on STARD13 3'UTR.
RESULTS: PUM2 and STARD13 expression was significantly decreased in OS tissues, and positively correlated. Overexpression of PUM2 or STARD13 3'UTR inhibited OS cells proliferation, migration, and stemness. Mechanistically, PUM2 competitively bound to STARD13 3'UTR with miR-590-3p and miR-9. The inhibition of PUM2 on OS cells progression was attenuated by STARD13 knockdown or related miRNAs overexpression.
CONCLUSION: PUM2 suppresses OS progression via partly and competitively binding to STARD13 3'UTR with miRNAs.
Zheng L, Zhang Z, Zhang S, et al.RNA Binding Protein RNPC1 Inhibits Breast Cancer Cell Metastasis via Activating STARD13-Correlated ceRNA Network.
Mol Pharm. 2018; 15(6):2123-2132 [PubMed
] Related Publications
RNA binding proteins (RBPs) are pivotal post-transcriptional regulators. RNPC1, an RBP, acts as a tumor suppressor through binding and regulating the expression of target genes in cancer cells. This study disclosed that RNPC1 expression was positively correlated with breast cancer patients' relapse-free and overall survival and that RNPC1 suppressed breast cancer cell metastasis. Mechanistically, RNPC1 promotes competing endogenous RNA (ceRNA) network crosstalk among STARD13, CDH5, HOXD10, and HOXD1 (STARD13-correlated ceRNA network), which we previously confirmed in breast cancer cells through stabilizing the transcripts and thus facilitating the expression of these four genes in breast cancer cells. Furthermore, RNPC1 overexpression restrained the promotion of STARD13, CDH5, HOXD10, and HOXD1 knockdown on cell metastasis. Notably, RNPC1 expression was positively correlated with CDH5, HOXD1, and HOXD10 expression in breast cancer tissues and attenuated adriamycin resistance. Taken together, these results identified that RNPC1 could inhibit breast cancer cell metastasis via promoting a STARD13-correlated ceRNA network.
Guo X, Xiang C, Zhang Z, et al.Displacement of Bax by BMF Mediates STARD13 3'UTR-Induced Breast Cancer Cells Apoptosis in an miRNA-Depedent Manner.
Mol Pharm. 2018; 15(1):63-71 [PubMed
] Related Publications
The balance of pro- and antiapoptotic gene expression programs dominates the apoptotic progress of cancer cells. We previously demonstrated that STARD13 3'UTR suppressed breast cancer metastasis via inhibiting epithelial-mesenchymal transition (EMT). However, the roles of STARD13 3'UTR in breast cancer apoptosis remain elusive. Here, we identified that STARD13 3'UTR promoted cell apoptosis in vitro and in vivo. Mechanistically, STARD13 3'UTR acted as a ceRNA for BMF (Bcl-2 modifying factor), thus increasing BMF expression in an miRNA-dependent manner. Meanwhile, STARD13 3'UTR enhanced the interaction of BMF/Bcl-2 to release Bax (Bcl-2 associated X protein) in breast cancer cells. Finally, we verified the ceRNA relationship between STARD13 and BMF in vivo. Collectively, these findings suggest that STARD13 3'UTR could act as a ceRNA for BMF to promote apoptosis and recognize STARD13 3'UTR as a potential therapeutic target in breast cancer cells.
Zheng L, Li X, Chou J, et al.StarD13 3'-untranslated region functions as a ceRNA for TP53INP1 in prohibiting migration and invasion of breast cancer cells by regulating miR-125b activity.
Eur J Cell Biol. 2018; 97(1):23-31 [PubMed
] Related Publications
Competitive endogenous messenger RNA (ceRNA) affects transcription of other RNA molecules by competitively binding common microRNAs. Previous studies have shown that TP53INP1 functions as a suppressor in tumor metastasis. Our study elucidated StarD13 messenger RNA as a ceRNA in regulating migration and invasion of breast cancer cells. MicroRNA-125b was identified to induce metastasis of MCF-7 cells and bind with both StarD13 3'UTR and TP53INP1 3'UTR. Therefore, a ceRNA interaction between StarD13 and TP53INP1 mediated by competitively binding to miR-125b was indicated. Importantly, a microRNA-125b binding site at 4546-4560 nt on StarD13 was verified more vital for this ceRNA interaction. Indirectly regulation of SPARC in inducing metastasis of breast cancer cells by StarD13 via competitively binding with TP53INP1 was further confirmed. In conclusion, our findings demonstrate a ceRNA regulatory network which could give a better understanding of metastatic mechanisms of breast cancer.
Diverse RNA transcripts acting as competing endogenous RNAs (ceRNAs) can co-regulate each other's expression by competing for shared microRNAs. CCR2 protein, the receptor for CCL2, is implicated in cancer progression. However, we found that a higher
Zhang H, Wang F, Hu YSTARD13 promotes hepatocellular carcinoma apoptosis by acting as a ceRNA for Fas.
Biotechnol Lett. 2017; 39(2):207-217 [PubMed
] Related Publications
OBJECTIVES: To study the roles of STARD13 in cellular apoptosis of hepatocellular carcinoma (HCC).
RESULTS: Quantitative real-time PCR and immunohistochemistry analyses showed that the expression levels of STARD13 and Fas were lower in clinical HCC tissues than in normal tissues and were positively correlated, which is consistent with the results analyzed by The Cancer Genome Atlas (TCGA) data. Patients with higher STARD13 or Fas expression levels had longer overall survival. Additionally, STARD13 3'-UTR enhanced cellular apoptosis and the 3'-UTRs of STARD13 and Fas were predicted to harbor nine similar miRNA binding sites. And STARD13 3'-UTR promoted Fas expression in a 3'-UTR- and miRNA-dependent way and increased the sensitivity of HCC cells to chemotherapy. Importantly, the coding sequence of STARD13 did not increase Fas expression.
CONCLUSIONS: STARD13 3'-UTR promotes HCC apoptosis through acting as a ceRNA for Fas.
Chang S, He S, Qiu G, et al.MicroRNA-125b promotes invasion and metastasis of gastric cancer by targeting STARD13 and NEU1.
Tumour Biol. 2016; 37(9):12141-12151 [PubMed
] Related Publications
MicroRNAs have been documented playing key roles in cancer development and progression. Here, we investigate the role of miR-125b in gastric cancer metastasis. We found that the expression of miR-125b was up-regulated in gastric cancer tissue specimens compared with their corresponding nontumorous tissues, and the up-regulated miR-125b level was significantly associated with TNM stage and lymph node-metastasis. Overexpression of miR-125b promoted gastric cancer cell migration and invasion in vitro and metastasis in vivo. STARD13 and NEU1 were identified as direct target genes of miR-125b by luciferase assays, and they were involved in the cell migration and invasion regulated by miR-125b in gastric cancer. Taken together, miR-125b functions as an oncogene in gastric cancer and represents a new potential therapeutic target for gastric cancer.
D'Ippolito E, Plantamura I, Bongiovanni L, et al.miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer.
Cancer Res. 2016; 76(18):5562-72 [PubMed
] Related Publications
Organization of cancer cells into endothelial-like cell-lined structures to support neovascularization and to fuel solid tumors is a hallmark of progression and poor outcome. In triple-negative breast cancer (TNBC), PDGFRβ has been identified as a key player of this process and is considered a promising target for breast cancer therapy. Thus, we aimed at investigating the role of miRNAs as a therapeutic approach to inhibit PDGFRβ-mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200. In MDA-MB-231 and MDA-MB-157 TNBC cell lines, miR-9 and miR-200 promoted and inhibited, respectively, the formation of vascular-like structures in vitro Induction of endogenous miR-9 expression, upon ligand-dependent stimulation of PDGFRβ signaling, promoted significant vascular sprouting of TNBC cells, in part, by direct repression of STARD13. Conversely, ectopic expression of miR-200 inhibited this sprouting by indirectly reducing the protein levels of PDGFRβ through the direct suppression of ZEB1. Notably, in vivo miR-9 inhibition or miR-200c restoration, through either the generation of MDA-MB-231-stable clones or peritumoral delivery in MDA-MB-231 xenografted mice, strongly decreased the number of vascular lacunae. Finally, IHC and immunofluorescence analyses in TNBC specimens indicated that PDGFRβ expression marked tumor cells engaged in vascular lacunae. In conclusion, our results demonstrate that miR-9 and miR-200 play opposite roles in the regulation of the vasculogenic ability of TNBC, acting as facilitator and suppressor of PDGFRβ, respectively. Moreover, our data support the possibility to therapeutically exploit miR-9 and miR-200 to inhibit the process of vascular lacunae formation in TNBC. Cancer Res; 76(18); 5562-72. ©2016 AACR.
The RHO family of RAS-related GTPases in tumors may be activated by reduced levels of RHO GTPase accelerating proteins (GAPs). One common mechanism is decreased expression of one or more members of the Deleted in Liver Cancer (DLC) family of Rho-GAPs, which comprises three closely related genes (DLC1, DLC2, and DLC3) that are down-regulated in a wide range of malignancies. Here we have studied their comparative biological activity in cultured cells and used publicly available datasets to examine their mRNA expression patterns in normal and cancer tissues, and to explore their relationship to cancer phenotypes and survival outcomes. In The Cancer Genome Atlas (TCGA) database, DLC1 expression predominated in normal lung, breast, and liver, but not in colorectum. Conversely, reduced DLC1 expression predominated in lung squamous cell carcinoma (LSC), lung adenocarcinoma (LAD), breast cancer, and hepatocellular carcinoma (HCC), but not in colorectal cancer. Reduced DLC1 expression was frequently associated with promoter methylation in LSC and LAD, while DLC1 copy number loss was frequent in HCC. DLC1 expression was higher in TCGA LAD patients who remained cancer-free, while low DLC1 had a poorer prognosis than low DLC2 or low DLC3 in a more completely annotated database. The poorest prognosis was associated with low expression of both DLC1 and DLC2 (P < 0.0001). In cultured cells, the three genes induced a similar reduction of Rho-GTP and cell migration. We conclude that DLC1 is the predominant family member expressed in several normal tissues, and its expression is preferentially reduced in common cancers at these sites.
Competing endogenous RNAs (ceRNAs) network has been correlated with the initiation and development of cancer. Here, we identify CDH5, HOXD1, and HOXD10 as putative STARD13 ceRNAs and they display concordant patterns with STARD13 in different metastatic potential breast cancer cell lines and tissues. Notably, 3'UTRs of these genes suppress breast cancer metastasis via inhibiting epithelial-mesenchymal transition (EMT) in vitro and in vivo, which are activated through the crosstalk between STARD13 and its ceRNAs in 3'UTR- and miRNA-dependent manners. In addition, Kaplan-Meier survival analysis reveals that mRNA level of STARD13 and its ceRNAs is remarkably associated with survival of breast cancer patients. These results suggest that 3'UTRs of CDH5, HOXD1, and HOXD10 inhibit breast cancer metastasis via serving as STARD13 ceRNAs.
Braun AC, Olayioye MARho regulation: DLC proteins in space and time.
Cell Signal. 2015; 27(8):1643-51 [PubMed
] Related Publications
Rho GTPases function as molecular switches that connect changes of the external environment to intracellular signaling pathways. They are active at various subcellular sites and require fast and tight regulation to fulfill their role as transducers of extracellular stimuli. New imaging technologies visualizing the active states of Rho proteins in living cells elucidated the necessity of precise spatiotemporal activation of the GTPases. The local regulation of Rho proteins is coordinated by the interaction with different guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that turn on and off GTPase signaling to downstream effectors. GEFs and GAPs thus serve as critical signaling nodes that specify the amplitude and duration of a particular Rho signaling pathway. Despite their importance in Rho regulation, the molecular aspects underlying the spatiotemporal control of the regulators themselves are still largely elusive. In this review we will focus on the Deleted in Liver Cancer (DLC) family of RhoGAP proteins and summarize the evidence gathered over the past years revealing their different subcellular localizations that might account for isoform-specific functions. We will also highlight the importance of their tightly controlled expression in the context of neoplastic transformation.
Wang X, Kuang Y, Shen X, et al.Evaluation of miR-720 prognostic significance in patients with colorectal cancer.
Tumour Biol. 2015; 36(2):719-27 [PubMed
] Related Publications
Aberrant expression of miR-720 had been reported in several cancers. However, the expression level and prognostic value of miR-720 in colorectal cancer (CRC) had not been addressed. In our study, we detected the expression level of miR-720 in 96 CRC tissues to evaluate its clinicopathological characteristics in colorectal cancer. Kaplan-Meier survival curve was performed to evaluate the prognostic role of miR-720 in patients with CRC. Furthermore, in vitro, we transfected the miR-720 mimics or inhibitors into the corresponding CRC cell lines and evaluated the effects on the abilities of cell growth, colony formation, migration, wound healing, and invasion in CRC cells. Our data showed that miR-720 level was significantly upregulated in CRC tissues than that in corresponding normal-appearing tissues (NATs) (p < 0.05), and high miR-720 correlated with the tumor size (p = 0.014), tumor-node-metastasis (TNM) stage (p = 0.040), lymphatic metastasis (p = 0.008), and distant metastasis (p = 0.016), which led to a poorer 5-year overall survival rate in CRC patients (p < 0.05). Our experiments in vitro also confirmed that miR-720 could promote the cell growth (p < 0.05), abilities of colony formation (p < 0.05), wound healing (p < 0.05), migration (p < 0.05), and invasion of CRC cells (p < 0.05). We identified StarD13 gene as a putative target of miR-720 in colorectal cancer by bioinformatics analysis, and subsequent dual luciferase activity and Western blot assay further certified that miR-720 might specifically target the StarD13 3'-untranslated region (UTR) at the 795 region (p < 0.05). miR-720 might act as a promoting factor in the development of CRC and could be a prognostic indicator in the prognosis of CRC. Downregulation of miR-720 might be considered to be a potentially important molecular treatment strategy for early stage CRC patients.
Bera A, VenkataSubbaRao K, Manoharan MS, et al.A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer.
PLoS One. 2014; 9(9):e106343 [PubMed
] Free Access to Full Article Related Publications
In this study a microRNA (miRNA) signature was identified in a gemcitabine resistant pancreatic ductal adenocarcinoma (PDAC) cell line model (BxPC3-GZR) and this signature was further examined in advanced PDAC tumor specimens from The Cancer Genome Atlas (TCGA) database. BxPC3-GZR showed a mesenchymal phenotype, expressed high levels of CD44 and showed a highly significant deregulation of 17 miRNAs. Based on relevance to cancer, a seven-miRNA signature (miR-100, miR-125b, miR-155, miR-21, miR-205, miR-27b and miR-455-3p) was selected for further studies. A strong correlation was observed for six of the seven miRNAs in 43 advanced tumor specimens compared to normal pancreas tissue. To assess the functional relevance we initially focused on miRNA-125b, which is over-expressed in both the BxPC3-GZR model and advanced PDAC tumor specimens. Knockdown of miRNA-125b in BxPC3-GZR and Panc-1 cells caused a partial reversal of the mesenchymal phenotype and enhanced response to gemcitabine. Moreover, RNA-seq data from each of 40 advanced PDAC tumor specimens from the TCGA data base indicate a negative correlation between expression of miRNA-125b and five of six potential target genes (BAP1, BBC3, NEU1, BCL2, STARD13). Thus far, two of these target genes, BBC3 and NEU1, that are tumor suppressor genes but not yet studied in PDAC, appear to be functional targets of miR-125b since knockdown of miR125b caused their up regulation. These miRNAs and their molecular targets may serve as targets to enhance sensitivity to chemotherapy and reduce metastatic spread.
Qian Z, Zhu G, Tang L, et al.Whole genome gene copy number profiling of gastric cancer identifies PAK1 and KRAS gene amplification as therapy targets.
Genes Chromosomes Cancer. 2014; 53(11):883-94 [PubMed
] Related Publications
Gastric cancer is the second leading cause of death from cancer worldwide, with an approximately 20% 5-year survival rate. To identify molecular subtypes associated with the clinical prognosis, in addition to genetic aberrations for potential targeted therapeutics, we conducted a comprehensive whole-genome analysis of 131 Chinese gastric cancer tissue specimens using whole-genome array comparative genomic hybridization. The analyses revealed gene focal amplifications, including CTSB, PRKCI, PAK1, STARD13, KRAS, and ABCC4, in addition to ERBB2, FGFR2, and MET. The growth of PAK1-amplified gastric cancer cells in vitro and in vivo was inhibited when the corresponding mRNA was knocked down. Furthermore, both KRAS amplification and KRAS mutation were identified in the gastric cancer specimens. KRAS amplification was associated with worse clinical outcomes, and the KRAS gene mutation predicted sensitivity to the MEK1/2 inhibitor AZD6244 in gastric cancer cell lines. In summary, amplified PAK1, as well as KRAS amplification/mutation, may represent unique opportunities for developing targeted therapeutics for the treatment of gastric cancer.
Breast cancer is one of the most commonly diagnosed cancers in women around the world. In general, the more aggressive the tumor, the more rapidly it grows and the more likely it metastasizes. Members of the Rho subfamily of small GTP-binding proteins (GTPases) play a central role in breast cancer cell motility and metastasis. The switch between active GTP-bound and inactive GDP-bound state is regulated by guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and guanine-nucleotide dissociation inhibitors (GDIs). We studied the role of StarD13, a recently identified Rho-GAP that specifically inhibits the function of RhoA and Cdc42. We aimed to investigate its role in breast cancer proliferation and metastasis. The levels of expression of this Rho-GAP in tumor tissues of different grades were assayed using immunohistochemistry. We observed that, while the level of StarD13 expression decreases in cancer tissues compared to normal tissues, it increases as the grade of the tumor increased. This was consistent with the fact that although StarD13 was indeed a tumor suppressor in our breast cancer cells, as seen by its effect on cell proliferation, it was needed for cancer cell motility. In fact, StarD13 knockdown resulted in an inhibition of cell motility and cells were not able to detach their tail and move forward. Our study describes, for the first time, a tumor suppressor that plays a positive role in cancer motility.
Malignant astrocytomas are highly invasive into adjacent and distant regions of the normal brain. Rho GTPases are small monomeric G proteins that play important roles in cytoskeleton rearrangement, cell motility, and tumor invasion. In the present study, we show that the knock down of StarD13, a GTPase activating protein (GAP) for RhoA and Cdc42, inhibits astrocytoma cell migration through modulating focal adhesion dynamics and cell adhesion. This effect is mediated by the resulting constitutive activation of RhoA and the subsequent indirect inhibition of Rac. Using Total Internal Reflection Fluorescence (TIRF)-based Förster Resonance Energy Transfer (FRET), we show that RhoA activity localizes with focal adhesions at the basal surface of astrocytoma cells. Moreover, the knock down of StarD13 inhibits the cycling of RhoA activation at the rear edge of cells, which makes them defective in retracting their tail. This study highlights the importance of the regulation of RhoA activity in focal adhesions of astrocytoma cells and establishes StarD13 as a GAP playing a major role in this process.
Nasrallah A, Saykali B, Al Dimassi S, et al.Effect of StarD13 on colorectal cancer proliferation, motility and invasion.
Oncol Rep. 2014; 31(1):505-15 [PubMed
] Related Publications
Colon cancer is a cancer of the epithelial cells lining the colon. It is mainly divided into different stages according to the invasiveness and metastatic ability of the tumor. Many mutations are acquired which leads to the development of this malignancy. These occur in entities that greatly affect the cell cycle, cell signaling pathways and cell motility, which all involve the action of Rho GTPases. The protein of interest in the present study was DLC2, also known as StarD13 or START-GAP2, a GTPase-activating protein (GAP) for Rho and Cdc42. Literature data indicate that this protein is considered a tumor-suppressor in hepatocellular carcinoma. Previous research in our laboratory confirmed StarD13 as a tumor suppressor in astrocytoma and in breast cancer. In the present study, we investigated the role of StarD13 in colon cancer. When overexpressed, StarD13 was found to lead to a decrease in cell proliferation in colon cancer cells. Consistently, knockdown of StarD13 led to an increase in cell proliferation. This showed that, similarly to its role in astrocytoma and breast cancer, StarD13 appears to be a tumor suppressor in colon cancer as well. We also examined the role of StarD13 in cell motility. StarD13 knockdown resulted in the inhibition of 2D cell motility. This was due to the inhibition of Rho; consequently Rac-dependent focal complexes were not formed nor detached for the cells to move forward. However, StarD13 knockdown led to an increase in 3D cell motility. Although StarD13 was indeed a tumor suppressor in our colon cancer cells, as evidenced by its effect on cell proliferation, it was required for cancer cell invasion. The present study further describes the role of StarD13 as a tumor suppressor as well as a Rho GAP.
Previous studies proposed that myosin-Va regulates apoptosis by sequestering pro-apoptotic Bmf to the actin cytoskeleton through dynein light chain-2 (DLC2). Adhesion loss or other cytoskeletal perturbations would unleash Bmf, allowing it to bind and inhibit pro-survival Bcl2 proteins. Here, we demonstrated that overexpression of a myosin-Va medial tail fragment (MVaf) harboring the binding site for DLC2 dramatically decreased melanoma cell viability. Morphological and molecular changes, including surface blebbing, mitochondrial outer membrane permeabilization, cytochrome-c and Smac release, as well as caspase-9/-3 activation and DNA fragmentation indicated that melanoma cells died of apoptosis. Immobilized MVaf interacted directly with DLCs, but complexed MVaf/DLCs did not interact with Bmf. Overexpression of DLC2 attenuated MVaf-induced apoptosis. Thus, we suggest that, MVaf induces apoptosis by sequestering DLC2 and DLC1, thereby unleashing the pair of sensitizer and activator BH3-only proteins Bmf and Bim. Murine embryonic fibroblasts (MEFs) lacking Bim and Bmf or Bax and Bak were less sensitive to apoptosis caused by MVaf expression than wild-type MEFs, strengthening the putative role of the intrinsic apoptotic pathway in this response. Finally, MVaf expression attenuated B16-F10 solid tumor growth in mice, suggesting that this peptide may be useful as an apoptosis-inducing tool for basic and translational studies.
MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression by targeting mRNAs to trigger either translation repression or mRNA degradation. miR-125b is down-regulated in human breast cancer cells compared with the normal ones except highly metastatic tumor cells MDA-MB-231. However, few functional studies were designed to investigate metastatic potential of miR-125b. In this study, the effects of miR-125b on metastasis in human breast cancer cells were studied, and the targets of miR-125b were also explored. Transwell migration assay, cell wound healing assay, adhesion assay and nude mice model of metastasis were utilized to investigate the effects of miR-125b on metastasis potential in vitro and in vivo. In addition, it was implied STARD13 (DLC2) was a direct target of miR-125b by Target-Scan analysis, luciferase reporter assay and western blot. Furthermore, activation of STARD13 was identified responsible for metastasis induced by miR-125b through a siRNA targeting STARD13. qRT-PCR, immunofluorescent assay and western blot was used to observe the variation of Vimentin and α-SMA in breast cancer cells. In summary, our study provided new insights into the function of miR-125b during the metastasis of breat cancer cells and also suggested the role of miR-125b in pro-metastasis by targeting STARD13.
El-Sitt S, Khalil BD, Hanna S, et al.DLC2/StarD13 plays a role of a tumor suppressor in astrocytoma.
Oncol Rep. 2012; 28(2):511-8 [PubMed
] Related Publications
Astrocytomas are tumors occurring in young adulthood. Astrocytic tumors can be classified into four grades according to histologic features: grades I, II, III and grade IV. Malignant tumors, those of grades III and IV, are characterized by uncontrolled proliferation, which is known to be regulated by the family of Rho GTPases. StarD13, a GAP for Rho GTPases, has been described as a tumor suppressor in hepatocellular carcinoma. In the present study, IHC analysis on grades I-IV brain tissues from patients showed StarD13 to be overexpressed in grades III and IV astrocytoma tumors when compared to grades I and II. However, when we mined the REMBRANDT data, we found that the mRNA levels of StarD13 are indeed higher in the higher grades but much lower than the normal tissues. Knocking down StarD13 using siRNA led to a decrease in cell death and an increase in cell viability, proving that StarD13 is indeed a tumor suppressor in astrocytomas. This was found to be mainly through cell cycle arrest independently of apoptosis. Finally, we detected an increase in p-ERK in StarD13 knockdown cells, uncovering a potential link between Rho GTPases and ERK activation.
BACKGROUND: Expression quantitative trait loci (eQTL) studies have helped identify the genetic determinants of gene expression. Understanding the potential interacting mechanisms underlying such findings, however, is challenging.
METHODS: We describe a method to identify the trans-acting drivers of multiple gene co-expression, which reflects the action of regulatory molecules. This method-termed co-regulatory expression quantitative trait locus (creQTL) mapping-allows for evaluation of a more focused set of phenotypes within a clear biological context than conventional eQTL mapping.
RESULTS: Applying this method to a study of endometrial cancer revealed regulatory mechanisms supported by the literature: a creQTL between a locus upstream of STARD13/DLC2 and a group of seven IFNβ-induced genes. This suggests that the Rho-GTPase encoded by STARD13 regulates IFNβ-induced genes and the DNA damage response.
CONCLUSIONS: Because of the importance of IFNβ in cancer, our results suggest that creQTL may provide a finer picture of gene regulation and may reveal additional molecular targets for intervention. An open source R implementation of the method is available at http://sites.google.com/site/kenkompass/.
Leung TH, Yam JW, Chan LK, et al.Deleted in liver cancer 2 suppresses cell growth via the regulation of the Raf-1-ERK1/2-p70S6K signalling pathway.
Liver Int. 2010; 30(9):1315-23 [PubMed
] Related Publications
BACKGROUND: Deleted in liver cancer 2 (DLC2) gene, a putative tumour suppressor gene, encodes a Rho GTPase-activating protein (RhoGAP) with GAP activity specific for RhoA. It exhibits tumour suppressor functions and inhibits tumour cell proliferation, migration as well as transformation.
AIMS: In this study, we aimed to investigate the underlying mechanisms of the DLC2 gene in suppressing cell migration and cell growth. HepG2 hepatoma cells were stably transfected with the DLC2γ isoform, which contains the RhoGAP domain.
METHODS AND RESULTS: On performing immunofluorescence staining and Western blot analysis, the expression of the focal adhesion protein paxillin was found to be much reduced in DLC2γ-stable clones. Upon flow cytometric analysis of the cell cycle profiles, the DLC2γ-stable clones were shown to have a higher population of cells arrested at the G1 phase than the EGFP vector-stable clone, suggesting that downregulation of RhoA activity in DLC2γ-stable clones inhibited cell cycle progression. In the DLC2γ-stable clone, the levels of Raf-1 and extracellular signal-regulated kinase (ERK) 1/2 were decreased as compared with those of the parental HepG2, EGFP vector and DLC2γ-GAP defective mutant-stable clones. Furthermore, the ribosomal kinase p70S6K, a downstream target of ERK1/2, was suppressed in the DLC2-stable clones. On the contrary, when DLC2 was knocked down by siRNA in HepG2 cells, the expression levels of phospho-p70S6K and phospho-ERK1/2 were upregulated.
CONCLUSION: Our data show that DLC2 inhibits the activity of Raf-1-ERK1/2-p70S6K via its RhoGAP function, resulting in the suppression of cell growth. Further studies on the molecular signalling between DLC2 and p70S6K may provide an insight into its growth suppressor function.
Niini T, López-Guerrero JA, Ninomiya S, et al.Frequent deletion of CDKN2A and recurrent coamplification of KIT, PDGFRA, and KDR in fibrosarcoma of bone--an array comparative genomic hybridization study.
Genes Chromosomes Cancer. 2010; 49(2):132-43 [PubMed
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Very little is known about the genetics of fibrosarcoma (FS) of bone. We applied array comparative genomic hybridization (CGH) to identify genes and genomic regions with potential role in the pathogenesis of this tumor. Seventeen patients with FS of bone were included in the study. Array CGH analysis was carried out in 13 fresh frozen tissue specimens from 11 of these patients (nine primary tumors and four local recurrences). DNA was extracted and hybridizations were performed on Agilent 244K CGH oligoarrays. The data were analyzed using Agilent DNA Analytics Software. The number of changes per patient ranged from 0 to 132 (average = 43). Losses were most commonly detected at 6q, 8p, 9p, 10, 13q, and 20p. CDKN2A was homozygously deleted in 7/11 patients. Hypermethylation of both p16(INK4a) and p14(ARF) was found in 1/14 patients. An internal deletion of STARD13 was found in a region with common losses at 13q13.1. The most frequent gains were seen at 1q, 4q, 5p, 8q, 12p, 15q, 16q, 17q, 20q, 22q, and Xp. Single recurrent high level amplification was detected at 4q12, including KIT, PDGFRA, and KDR. No activating mutations were found in any of them. Immunohistochemistry revealed expression of PDGFRA and/or PDGFRB in 12/17 samples. Moreover, small regions of gains pinpointed genes of particular interest, such as IGF1R at 15q26.3 and CHD1L at 1q21.1. In conclusion, our analysis provided novel findings that can be exploited when searching for markers for diagnosis and prognosis, and targets of therapy in this tumor type.
de Tayrac M, Etcheverry A, Aubry M, et al.Integrative genome-wide analysis reveals a robust genomic glioblastoma signature associated with copy number driving changes in gene expression.
Genes Chromosomes Cancer. 2009; 48(1):55-68 [PubMed
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Glioblastoma multiforme shows multiple chromosomal aberrations, the impact of which on gene expression remains unclear. To investigate this relationship and to identify putative initiating genomic events, we integrated a paired copy number and gene expression survey in glioblastoma using whole human genome arrays. Loci of recurrent copy number alterations were combined with gene expression profiles obtained on the same tumor samples. We identified a set of 406 "cis-acting DNA targeted genes" corresponding to genomic aberrations with direct copy-number-driving changes in gene expression, defined as genes with either significantly concordant or correlated changes in DNA copy number and expression. Functional annotation revealed that these genes participate in key processes of cancer cell biology, providing insights into the genetic mechanisms driving glioblastoma. The robustness of the gene selection was validated on an external microarray data set including 81 glioblastomas and 23 non-neoplastic brain samples. The integration of array CGH and gene expression data highlights a robust cis-acting DNA targeted genes signature that may be critical for glioblastoma progression, with two tumor suppressor genes PCDH9 and STARD13 that could be involved in tumor invasiveness and resistance to etoposide.
BACKGROUND: DLC2, a unique RhoGAP, has been recently identified as a tumor suppressor gene in hepatocellular carcinoma (HCC). However, the expression of DLC2 protein, and its relationship with RhoA in clinical hepatocellular carcinoma have not been studied. The aim of this study was to investigate the DLC2 protein expression and its correlation with expression of RhoA, as well as to evaluate the prognostic value of DLC2 for HCC patients.
METHODS: Western blot and immunohistochemical staining were employed to detect DLC2 protein expression in 128 HCC specimens. The correlation between DLC2 protein expression and clinicopathologic outcome, and prognostic value of DLC2 for HCC patients were analyzed.
RESULTS: HCC tissues revealed significantly lower level of DLC2 protein than pericarcinomatous liver tissues (PCLT). There was significant correlation between underexpression of DLC2 protein and cell differentiation. Meanwhile, underexpression of DLC2 protein was correlated with overexression of RhoA. Furthermore, HCC Patients with DLC2-negative expression showed a significantly poorer prognosis than those with DLC2-positve expression.
CONCLUSION: Our data strongly suggested that decreased DLC2 expression in HCC correlates with cell differentiation of HCC and overexpression of RhoA, underexpression of DLC2 is associated with poor prognosis in HCC patients.
Ullmannova V, Popescu NCExpression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors.
Int J Oncol. 2006; 29(5):1127-32 [PubMed
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Several years after the isolation of deleted in liver cancer 1 (DLC-1), a gene that encodes a Rho GTPase activating protein, the closely related DLC-2 gene was identified. DLC-1 and DLC-2 are approximately 50% identical and share the same SAM-RhoGAP-START domain organization. Since DLC-1 and -2 are located at chromosome regions that are commonly deleted in cancer cells and have been found to function as tumor suppressor genes, we sought to compare their expression profiles in several common types of cancer and to determine whether dlc1 and dlc2 proteins cooperate in tumor development. Using cancer-profiling arrays, we detected for the first time down-regulation of DLC-1 expression in renal, uterine and rectal cancers and down-regulation of DLC-2 expression in lung, ovarian, renal, breast, uterine, gastric, colon and rectal tumors. Since DLC-1 also functions as a metastasis suppressor gene in breast cancer, DLC-1 and DLC-2 expression were examined in a series of primary ductal carcinomas derived from patients with regional lymph node metastases. Using quantitative RT-PCR we detected a significantly lower expression of DLC-1 and DLC-2 in high percentage of tumors, suggesting that deficiency of either DLC gene facilitates dissemination of breast carcinoma cells to secondary sites. We examined DLC-2 expression in DLC-1-negative cell lines derived from human breast, non-small cell lung, and hepatocellular carcinomas, that could be rendered less or non-tumorigenic by ectopic expression of DLC-1. DLC-2 transcripts were detected in all cell lines, indicating that none of the cells were deficient in both members of the DLC family. This comparative expression analysis of DLC-1 and -2 identifies down-regulation of the two emerging bona fide tumor suppressor genes in additional types of solid tumors. The large spectrum of cancers with dysregulated DLC genes underlines the involvement of this family of genes in cancer development.
The deleted in liver cancer 2 (DLC2) gene, located at chromosome 13q12.3, is a recently identified tumor suppressor gene. The gene is frequently underexpressed in human hepatocellular carcinoma, and its chromosomal region shows frequent deletion. DLC2 encodes a unique RhoGTPase-activating protein (RhoGAP) specific for small RhoGTPases, RhoA, and Cdc42. With bioinformatic analysis, we have identified four different isoforms of DLC2, which we named DLC2alpha, DLC2beta, DLC2gamma, and DLC2delta. Three of the isoforms contain the RhoGAP domain, namely, DLC2alpha, DLC2beta, and DLC2gamma. Ectopic expression of these three isoforms in mouse fibroblasts showed cytoplasmic localization. Of interest, overexpression of these isoforms suppressed the lysophosphatidic acid-induced stress fiber formation in mouse fibroblasts and changed the morphology of the transfected cells from angular and spindle to round. Furthermore, the RhoA pull-down assay demonstrated a remarkable reduction in RhoA activity in the DLC2 transiently transfected cells. In contrast, cells transfected with inactive DLC2 GAP-mutant remained unchanged in cell morphology, actin stress fiber formation, and RhoA activity. HepG2 hepatoma cells stably transfected with the DLC2gamma isoform also changed to a round morphology, as in mouse fibroblasts. Of significance, these DLC2gamma stable transfectants showed marked suppression in cell proliferation, motility, and transformation, and there was a remarkable reduction in in vivo RhoA activity in these cells. These results suggest that DLC2 exhibits its tumor suppressor functions in vivo as a GAP specific for RhoA, exerting its effects in suppression of cytoskeleton reorganization, cell growth, cell migration, and transformation.
Morales AA, Olsson A, Celsing F, et al.Expression and transcriptional regulation of functionally distinct Bmf isoforms in B-chronic lymphocytic leukemia cells.
Leukemia. 2004; 18(1):41-7 [PubMed
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Bmf is a BH3-only Bcl-2 family member that is normally sequestered to myosin V motors by binding to the dynein light chain 2 (DLC2). Certain damage signals release Bmf, which then binds prosurvival Bcl-2 proteins and triggers apoptosis. Here, two novel isoforms of human Bmf, Bmf-II and Bmf-III, were identified and cloned from cDNA derived from B-chronic lymphocytic leukemia (B-CLL) cells. Bmf-II and Bmf-III were characterized as two splice variants, lacking the BH3 domain but retaining the DLC2 binding domain. Bmf (here called Bmf-I) expression in HeLa cells induced apoptosis and reduced colony formation in contrast to Bmf-II and Bmf-III, which had no effect on apoptosis and instead increased colony formation. While bmf-I mRNA was expressed in many cell types, expression was higher in B lymphoid cells and bmf-II and bmf-III were mainly detected in B-CLL and normal B cells. bmf-I mRNA was upregulated in normal and leukemic B cells, while bmf-III mRNA was downregulated only in B-CLL cells by serum deprivation. We show that Bmf is regulated by transcriptional activation and alternative splicing and conclude that the relative levels of Bmf isoforms may have a role in regulating growth and survival in B cells and leukemic B-CLL cells.