Cell Survival Is Regulated via SOX9/BCL2L1 Axis in HCT-116 Colorectal Cancer Cell Line

Abstract

Colorectal cancer (CRC) is one of the most frequent types of malignancies and one of the major causes of cancer-related death worldwide. Sex-determining region Y (SRY)-box 9 protein (SOX9) is a member of the SOX family of transcription factors which are involved in the regulation of differentiation and development. Recently, several reports suggest an important role of SOX9 in tumorigenesis since its overexpression correlates with tumor progression and poor outcome in several types of cancer; however, its role in CRC is not clear until now. Therefore, in this work, we searched for novel SOX9-regulated genes involved in cell survival of CRC. We silenced SOX9 in the poorly differentiated HCT-116 cell line, using a specific siRNA, to identify differential expressed genes by DNA microarrays and analyzed the role or candidate genes in apoptosis and autophagy. Transcriptome analysis showed that diverse cellular pathways, associated with CRC carcinogenesis such as Wnt/β-catenin, MAPK, TGF-β, and mTOR, were modulated after SOX9 silencing. Interestingly, we found that SOX9 silencing promotes downregulation of BCL2L1 and overexpression of CASP3, proteins related to apoptosis, which was further confirmed in SW-480, a moderated-differentiated cell line, but not in HT-29, well-differentiated cell line. Moreover, inhibition of BCL2L1 by ABT-737 (BH3 mimetic) in SOX9-silenced HCT-116 cells resulted in an increased apoptosis percentage. However, downregulation of BCL2L1 was not enough to induce autophagy. This is the first report, suggesting that cell survival in poorly and moderated-differentiated CRC cells lines is regulated by SOX9/BCL2L1 axis, but not in well-differentiated cell lines.

Network Pharmacology and bioinformatics analyses identify intersection genes of niacin and COVID-19 as potential therapeutic targets

“…BCL2L1 is an oncogenic driver and antiapoptotic factor in CRC [ 49–50 ]. It was reported that the induction of BCL2L1 led to a reduction of apoptosis in CRC cell lines [ 51 ]. These findings indicated that these 14 intersection genes might be potent pharmacological targets of niacin against CRC and COVID-19.…”

Clinicopathological and prognostic significance of SOX9 expression in gastric cancer patients: A meta-analysis

“…[15] In accordance with its function, large amounts of studies have explored the function of SOX9 expression in hepatocellular carcinoma, breast cancer, prostate cancer, lung cancer, esophageal cancer and colorectal cancer. [22,48–54] Moreover, a previous study found that H. pylori induces SOX9 expression in pretumorigenic gastric mouse cells. [11] Most recently, SOX9 expression also have received widespread attention in GC.…”

“…In addition, the Wnt/SOX9 signaling pathway affects cell proliferation, differentiation, apoptosis, invasion and migration, such as colorectal cancer and stem cells. [ 9 , 12 ] During the past few years, numerous evidence have revealed that SOX9 have oncogenic properties and upregulated expression of SOX9 was correlated with poor prognosis in patients with malignant tumors, including prostate cancer, [ 13 , 14 ] ovarian cancer, [ 15 ] breast carcinoma, [ 16 , 17 ] non-small cell lung cancer (NSCLC), [ 18 , 19 ] esophageal cancer, [ 20 , 21 ] colorectal cancer, [ 22 ] osteosarcoma [ 23 , 24 ] and glioma. [ 25 ] Growing evidence shows that SOX9 is associated with clinical TNM stage and indicates that SOX9 promotes migration, invasion [ 26 ] and the EMT process through the Wnt/β-catenin pathway.…”

SOX9 is associated with advanced T-stages of clinical stage II colon cancer in young Mexican patients

“…Immunofluorescence analysis. Immunofluorescence was performed 48 h post-transfection as previously described (34). Briefly, cells were washed with ice-cold PBS and fixed in 4% p-formaldehyde for 10 min.…”