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TCF12 protein functions as transcriptional repressor of E-cadherin, and its overexpression is correlated with metastasis of colorectal cancer.

ABSTRACT: A correlation of TCF12 mRNA overexpression with colorectal cancer (CRC) metastasis was suggested by microarray data and validated by the survey of 120 patients. Thirty-three (27.5%) of the 120 patients showed tumor TCF12 mRNA overexpression and had a higher rate of metastatic occurrence (p = 0.020) and a poorer survival outcome (p = 0.014). Abundant TCF12 levels were also observed in human CRC cell lines such as SW620 and LoVo, but a relatively low level was detected in SW480 cells. Knockdown of TCF12 expression in SW620 and LoVo cells drastically reduced their activities of migration, invasion, and metastasis. Tight cell-cell contact and an increase in E-cadherin but a concomitant decrease in fibronectin were observed in TCF12-knockdown cells. Connexin 26, connexin 43, and gap-junction activity were also increased upon TCF12-knockdown. In contrast, ectopic TCF12 overexpression in SW480 cells facilitated fibronectin expression and cell migration and invasion activities but diminished cellular levels of E-cadherin, connexin 26, connexin 43, and gap junction. A physical association of TCF12 with the E-cadherin promoter was evidenced by chromatin immunoprecipitation assay. TCF12 was tightly correlated with cellular expression of Bmi1 and EZH2 and was co-immunoprecipitable with Bmi1 and EZH2, suggesting that TCF12 transcriptionally suppressed E-cadherin expression via polycomb group-repressive complexes. Clinically, TCF12 mRNA overexpression was also correlated with E-cadherin mRNA down-regulation in the tumor tissues of our 120 patients (p = 0.013). These studies suggested that TCF12 functioned as a transcriptional repressor of E-cadherin and its overexpression was significantly correlated with the occurrence of CRC metastasis.

SUBMITTER: Lee CC

PROVIDER: S-EPMC3268437 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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TCF12 protein functions as transcriptional repressor of E-cadherin, and its overexpression is correlated with metastasis of colorectal cancer.

Lee Chun-Chung CC Chen Wei-Shone WS Chen Chia-Chi CC Chen Li-Li LL Lin Yi-Shing YS Fan Chi-Shuan CS Huang Tze-Sing TS

The Journal of biological chemistry 20111130 4

A correlation of TCF12 mRNA overexpression with colorectal cancer (CRC) metastasis was suggested by microarray data and validated by the survey of 120 patients. Thirty-three (27.5%) of the 120 patients showed tumor TCF12 mRNA overexpression and had a higher rate of metastatic occurrence (p = 0.020) and a poorer survival outcome (p = 0.014). Abundant TCF12 levels were also observed in human CRC cell lines such as SW620 and LoVo, but a relatively low level was detected in SW480 cells. Knockdown of ...[more]

PMID: 22130667

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Project description:BACKGROUND:Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in men and women. The presence of systemic disease, with metastatic spread to distant sites such as the liver, considerably reduces the survival rate in CRC. Cancer stem cells contribute to the metastatic potential of CRC. However, the mechanism underlying metastasis in CRC remains unclear. Thus, this study aimed to examine the expression of microRNAs (miRNAs) in CRC stem cells in cases of liver metastases and assess their correlation with clinicopathological features. METHODS:miRNAs showing high expression in liver metastases and primary lesions were selected through data mining of gene expression omnibus datasets, and miRNAs characteristic of stem cells were selected through COREMINE medical text mining. Subsequently, paired formalin-fixed paraffin-embedded tissue samples of primary CRC and liver metastasis from 30 patients were examined for the expression of miRNAs common to these lists (hsa-miR-20a, hsa-miR-26b, hsa-miR-146a, hsa-miR-17, hsa-miR-451, hsa-miR-23a, and hsa-miR-29a) using quantitative real-time polymerase chain reaction. Further, miRNA expression was compared between liver metastases and the primary tumor in each patient and the factors associated with differential expression were analyzed. RESULTS:hsa-miR-17 was significantly upregulated in liver metastases (P < .05), but no significant difference in the expression of hsa-miR-26b, hsa-miR-146a, hsa-miR-451, hsa-miR-23a, and hsa-miR-29a was observed between primary tumors and liver metastases. The higher expression of hsa-miR-17 in liver metastases was associated with the administration of neoadjuvant chemotherapy and tumor differentiation (P < .05) but was not associated with age, sex, tumor location, or lymphatic metastasis. CONCLUSIONS:High expression of miR-17 may contribute to liver metastasis in CRC. Therefore, an in-depth understanding of its downstream pathways could help in elucidating the mechanisms underlying liver metastases in CRC. However, additional studies are warranted to validate these findings.

Project description:BackgroundThe carboxyl terminus of Hsc70-interacting protein (CHIP) is an E3 ubiquitin ligase that plays a controversial role in different cancers, either as a tumor suppressor or a tumor promoter. To date, the exact function and underlying mechanism of CHIP in colorectal cancer (CRC) is not yet clear. Here we aimed to determine whether CHIP could affect the biological behaviors of CRC cells and its underlying mechanisms.MethodsStably transfected CHIP overexpression and depletion DLD-1 and HT-29 cells were established using Lipofectamine 2000. Cell growth was monitored by x-Celligence system. Cell proliferation was detected using CCK-8 and Brdu proliferation assay. Cell apoptosis and cell cycle were detected by flow cytometry analysis. Cell migration and invasion abilities were monitored by x-Celligence system, wound healing assay and transwell assay. In vivo intraperitoneal metastasis assay was performed to investigate the influence of CHIP on the tumor metastasis of CRC cells in nude mice. The expression of ERK, AKT, NF-кB signaling subunits and EMT related proteins were detected by Western blotting. The influence and function of CHIP on the protein expression of CRC cells were also elucidated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. CRC microarray tissue was analyzed to investigate the CHIP expression and its clinical significance.ResultsCHIP depletion inhibited cell growth, migration and invasion potential of CRC cells, accompanied by downregulation of MAPK and AKT signaling activities and upregulation of E-cadherin. CHIP overexpression dramatically enhanced the migration and invasion abilities, due to the upregulation of MAPK and AKT signaling and downregulation of E-cadherin. The proteomic analysis confirmed that E-cadherin was decreased in CHIP-overexpressing CRC cells. Furthermore, clinical tissue data revealed that CHIP expression was upregulated in CRC samples and was significantly correlated with poor survival of CRC patients. Mechanically, CHIP probably activated the MAPK and AKT signaling, which inactivated GSK-3β. The GSK-3β inactivation, in turn, upregulated Slug and led to E-cadherin downregulation and EMT initiation.ConclusionsOur finding suggested that CHIP functions as an oncogene in the migration and metastasis of CRC, and is a potential unfavorable independent predictive biomarker for CRC. CHIP activates the AKT pathway to promote EMT and metastasis in CRC through the CHIP-MAPK/AKT-GSK-3β-Slug-E-cadherin pathways.

Dataset Information

TCF12 protein functions as transcriptional repressor of E-cadherin, and its overexpression is correlated with metastasis of colorectal cancer.

Publications

TCF12 protein functions as transcriptional repressor of E-cadherin, and its overexpression is correlated with metastasis of colorectal cancer.

Similar Datasets

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