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.
Highlights
Colorectal cancer (CRC) is a multifactorial disease that results from lifestyle, genetic, and environmental factors [1], and it is considered as one of the major causes of cancerrelated death worldwide [2]
The intrinsic pathway is mitochondria-dependent mediated by intracellular signals in response to different stress conditions including Journal of Oncology chemotherapeutic agents, DNA damage, growth factor deprivation, and oxidative stress, among others [9]. e activation of intrinsic apoptosis pathway drives to apoptosome formation, which is composed of procaspase-9, apoptotic protease-activating factor (Apaf-1), and cytochrome c, that concludes in caspase-9 activation [5]. is process is led by Bcl-2 family members’ proteins that can be divided into two groups: proapoptotic or antisurvival (Bax, Bak, Bid, Bad, and Bok) and antiapoptotic or prosurvival (Bcl-2, Bcl-w, and Bcl-xL) [10]
Bax drives to apoptosome formation and caspase-3 activation, promoting apoptosis and has been reported that Bcl-xL, encoded by BCL2L1 (BCL2-like 1) gene [11], is able to stabilize the mitochondrial localization of Bax, maintaining it in an inactive state [12], which is a mechanism implicated in cell survival in different tumor types [13]
Summary
Colorectal cancer (CRC) is a multifactorial disease that results from lifestyle, genetic, and environmental factors [1], and it is considered as one of the major causes of cancerrelated death worldwide [2]. E extrinsic pathway is stimulated by interaction of ligands to cell surface-exposed death receptors that culminates in caspase activation, for example, the tumor necrosis factor receptors (TNFRs) and their respective protein TNF family ligand, among others [8]. E activation of intrinsic apoptosis pathway drives to apoptosome formation, which is composed of procaspase-9, apoptotic protease-activating factor (Apaf-1), and cytochrome c, that concludes in caspase-9 activation [5]. Bax drives to apoptosome formation and caspase-3 activation, promoting apoptosis and has been reported that Bcl-xL, encoded by BCL2L1 (BCL2-like 1) gene [11], is able to stabilize the mitochondrial localization of Bax, maintaining it in an inactive state [12], which is a mechanism implicated in cell survival in different tumor types [13]. Overexpression and mutation of SOX9 increases cell proliferation, invasiveness, and metastasis in several types of cancer [18,19,20,21]; little is known about SOX9 and its importance in cell survival in CRC. erefore, the aim of this study was to identify novel genes regulated by SOX9 and their role in cell survival in CRC
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