FOXO1 and TCF7L2 genes involved in metastasis and poor prognosis in clear cell renal cell carcinoma

Abstract

The goal of this study was to identify genes related to the metastasis of clear cell renal cell carcinoma (CRCC). We analyzed copy number alterations in renal tissue specimens of patients with CRCC patients with or without metastasis by using high-resolution single-nucleotide polymorphism (SNP) arrays and then integrated these data with gene expression profiling data obtained using oligonucleotide microarrays. The expression levels of target genes were determined by quantitative real-time RT-PCR (qRT-PCR) with an independent tumor set. An analysis of specimens from 23 CRCC cases with SNP arrays revealed that hemizygous deletions at 10q and 13q were found only in cases of metastatic disease. We found the homozygous deletion of TCF7L2 at 10q25.2 in an aggressive case that had hemizygous deletions at 10q. In addition, a qRT-PCR analysis of TCF7L2 mRNA levels in tumor samples revealed significantly lower levels in patients with metastasis when compared with those without metastasis. FOXO1 was identified as a down-regulated gene in the minimal overlapping region of the 13q hemizygous deletion in CRCC. Decreased FOXO1 expression was significantly correlated with metastasis and poor survival outcome. Knockdown of FOXO1 inhibited apoptosis after doxorubicin treatment in CRCC cells and reduced the expression of downstream genes involved in cell proliferation (CDKN1B) and survival (BCL2L11). Lower levels of FOXO1 expression were associated with decreased expression of CDKN1B and BCL2L11 in CRCC specimens. We conclude that FOXO1 and TCF7L2 are involved in metastasis and that molecules in these signaling pathways may be targets for diagnostic procedures and therapies for CRCC.

FOXO1 is a tumor suppressor in classical Hodgkin lymphoma

“…23 Of note, hemizygous FOXO1 deletions were reported to be associated with FOXO1 repression in clear cell renal cell carcinoma. 47 In conclusion, our data indicate that repression of FOXO1 transcription adds to autonomous growth and sustained survival of HRS cells of cHL. The mechanisms of FOXO1 repression in cHL are complex and include activation of ERK and AKT kinases, up-regulation of the miR-182, miR-96, and miR-183, and chromosome aberrations.…”

Revealing the molecular mechanism of colorectal cancer by establishing LGALS3-related protein-protein interaction network and identifying signaling pathways

“…MYC was activated in colorectal cancer and the overexpression pattern was identified as a downstream step at the end of the Wnt/APC/β-catenin signaling pathways is crucial in human cancer (42,43). The TCF7L2 gene has been shown to be involved in renal cell carcinoma metastasis (44). Members of the FOXO transcription family were involved in several cell processes, including apoptosis, stress resistance, metabolism, cell cycle, and DNA repair (45,46).…”

Competing endogenous RNA (ceRNA) cross talk and language in ceRNA regulatory networks: A new look at hallmarks of breast cancer

“…This reflects a cross talk between FOXO1 and E‐cadherin for suppressing BC through miR‐9 inactivating. FOXO1 is a transcription factor belonging to the the FOXO family, which has breast tumor suppressor roles (Zeng et al, ) and its upregulation is linked to good prognosis in BC (Kojima et al, ; Y. Wu, Elshimali, et al, ). In terms of miR‐9, Gwak et al () indicated that it is an oncogene which induces metastasis of BC via reducing the E‐cadherin expression and promoting EMT.…”