Overexpression of Forkhead Box C1 Promotes Tumor Metastasis and Indicates Poor Prognosis in Hepatocellular Carcinoma

Newberg

Proc. Natl. Acad. Sci. U.S.A.

et al. 2016

Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT-related transcription factors (EMTTFs). Sequencing of transposon insertion sites from tumors identified 233 candidate cancer genes (CCGs) that were enriched for genes and cellular processes driving EMT. Subsequent trunk driver analysis identified 23 CCGs that are predicted to function early in tumorigenesis and whose mutation or alteration in patients with HCC is correlated with poor patient survival. Validation of the top trunk drivers identified in the screen, including MET (MET proto-oncogene, receptor tyrosine kinase), GRB2-associated binding protein 1 (GAB1), HECT, UBA, and WWE domain containing 1 (HUWE1), lysine-specific demethylase 6A (KDM6A), and protein-tyrosine phosphatase, nonreceptor-type 12 (PTPN12), showed that deregulation of these genes activates an EMT program in human HCC cells that enhances tumor cell migration. Finally, deregulation of these genes in human HCC was found to confer sorafenib resistance through apoptotic tolerance and reduced proliferation, consistent with recent studies showing that EMT contributes to the chemoresistance of tumor cells. Our unique cell-based transposon mutagenesis screen appears to be an excellent resource for discovering genes involved in EMT in human HCC and potentially for identifying new drug targets.H CC is the sixth most common cancer and the third-leading cause of cancer-related deaths worldwide (1). In the United States, the incidence of HCC is increasing, and overall 5-y survival is now <12%, despite recent progress in diagnostic and therapeutic modalities (2). This high mortality rate is related mainly to a high recurrence rate and associated intrahepatic or extrahepatic metastases (1). Patients with HCC who develop metastasis are no longer eligible for liver transplantation therapy and have very limited therapeutic options. Currently, sorafenib is the sole systemic antineoplastic agent for HCC described in the National Comprehensive Cancer Network (NCCN) guideline (3); however, its clinical benefit is limited (4), and alternative effective treatments are needed for these patients.Epithelial-mesenchymal transition (EMT) is a complex differentiation process whereby epithelial cells lose their identity and acquire mesenchymal characteristics (5). EMT is observed routinely in developmental processes, but is also believed to play an important role in the migration, invasion, and metastasis of various cancers (6-9). It also promotes the generation of cancer stem cells, thereby contributing to tumor recurrence and metastasis...

mentioning

confidence: 99%

Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

Newberg

Proc. Natl. Acad. Sci. U.S.A.

et al. 2016

“…Forkhead box Q1 (FOXQ1, also termed HFH1) is a member of the forkhead transcription factor family (9), which is involved in a variety of biological processes, including epithelial differentiation (10), cell cycle progression (11), embryonic stem cell differentiation (12), metabolism (13,14) and carcinogenesis (15)(16)(17). As one of the first forkhead genes to be investigated, FOXQ1 has been demonstrated to be involved in metabolism, aging (18) and carcinogenesis (19).…”

Section: Introductionmentioning

confidence: 99%

FOXQ1 is overexpressed in laryngeal carcinoma and affects cell growth, cell cycle progression and cell invasion

Zhang

Song

et al. 2015

Oncology Letters

Abstract. Forkhead box Q1 (FOXQ1) is a forkhead transcription factor that is involved in numerous biological processes and has been shown to participate in tumorigenesis. However, the clinical significance of the expression of this protein in laryngeal carcinoma, and the mechanisms underlying its regulation in this disease remain unclear. The aim of present study was to measure the expression of FOXQ1 in laryngeal carcinoma, and to examine its effect on tumorigenesis. In the present study, reverse transcription-quantitative polymerase chain reaction and western blotting were employed to measure FOXQ1 expression in laryngeal carcinoma tissue samples, small interfering RNA specific to FOXQ1, was transfected into Hep2 cells and its effect on cell proliferation, cell cycle progression and cell migration was examined, using a CCK-8 assay, flow cytometry and a transwell migration assay, respectively. The results showed overexpression of FOXQ1 mRNA and protein in laryngeal cancer tissue samples. Inhibition of FOXQ1 suppressed cell growth and invasion, and arrested cells in the G0/G1 phase. Overexpression of FOXQ1 is associated with the development of laryngeal carcinoma and may enhance tumorigenesis through its effects on cell proliferation, cell cycle progression and cell migration.

“…In preliminary studies (11)(12)(13), EMT was verified to be involved in the cascade of signaling events inducing HCC metastasis (14,15). However, the concrete mechanisms of induction of EMT in HCC remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Metastasin leads to poor prognosis of hepatocellular carcinoma through partly inducing EMT

Zheng

Gai

et al. 2013

Oncology Reports

Abstract. Hepatocellular carcinoma (HCC) is a common malignant cancer worldwide characterized by high metastatic potential and poor prognosis following radical resection. Metastasin is a Ca 2+ -binding protein associated with tumor metastasis. However, the expression and function of metastasin remain unknown. In the present study, we found that the expression of metastasin was upregulated in HCC tissues and positively correlated with poor prognosis following radical resection. Ectopic expression of metastasin in vitro induced typical epithelial-mesenchymal transition (EMT) in Hep3B cells including higher capacity of both migration and invasion, increased expression of both Vimentin and N-cadherin and decreased expression of E-cadherin. Knockdown of metastasin produced the opposite results in MHCC97H cells, which indicates that metastasin promotes HCC progression via induction of EMT. SNAI1 expression was upregulated by enforced expression of metastasin and, consequently, suppressing upregulation of SNAI1 secondary to metastasin overexpression abolished EMT. Collectively, the present results suggest that metastasin leads to HCC EMT partly through upregulating SNAI1 and contributes to poor prognosis following radical liver resection. IntroductionHepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is the third leading cause of cancerrelated mortality worldwide (1). High frequency of intrahepatic and extrahepatic metastasis in the early stage contributes to the poor prognosis of HCC patients, which is also the vital factor involved in the disappointing survival following curative liver resection (2). Therefore, it is necessary to establish the factors that act as HCC metastatic markers, while playing an important role in the process of metastasis.Metastasin, also known as S100A4, belongs to the S100 family of Ca 2+ -binding proteins encoded by the mts1 gene (3,4). Although the relationship between metastasin and tumor metastasis remains unclear, previous investigations in experimental animal models indicated that metastasin is a metastasis factor via enhancing tumor angiogenesis (5), invasion (6) and motility (7). To our knowledge, metastasin expression is diverse in different organs. High metastasin expression has been found in human monocytes, macrophages and polymorphonuclear granulocytes (8), while low level of metastasin protein was detected in the pancreas, colon, thyroid, lung and kidney (9). However, only few investigations have demonstrated the expression and function of metastasin in liver and HCC.Epithelial mesenchymal transition (EMT) is a program of cancer metastasis which has been characterized as loss of epithelial cell polarity and acquisition of elongated mesenchymal morphology, concomitant with disruption of cell adhesion, increased cell migration, invasion and metastasis (10). In preliminary studies (11-13), EMT was verified to be involved in the cascade of signaling events inducing HCC metastasis (14,15). However, the concrete mechanisms of induction of EMT in HCC r...