Anti-oncogenic effects of SOX2 silencing on hepatocellular carcinoma achieved by upregulating miR-222-5p-dependent CYLD via the long noncoding RNA CCAT1

Abstract

In this study, we determined the involvement of SOX2 and its downstream signaling molecules in hepatocellular carcinoma (HCC) progression. We carried out lentiviral transfection in HepG2 cells to determine the roles of SOX2, CCAT1, EGFR, miR-222-5p, and CYLD in HepG2 cells. We first determined the interaction between SOX2 and CCAT1 and that between miR-222-5p and CYLD and their effect on tumor growth in vivo was analyzed in HCC-xenograft bearing nude mice xenografts. SOX2 and CCAT1 were highly expressed in HCC tissues and HepG2 cells. SOX2 bound to the regulatory site of CCAT1. Silencing of SOX2 or CCAT1 inhibited HepG2 cell proliferation, migration, and invasion as well as decreased the expression of CCAT1 and EGFR. CCAT1 silencing reduced EGFR expression, but EGFR expression was increased in HCC tissues and HepG2 cells, which promoted proliferation, migration, and invasion in vitro . EGFR upregulated miR-222-5p, leading to downregulation of CYLD. miR-222-5p inhibition or CYLD overexpression repressed cell functions in HepG2 cells. SOX2 silencing decreased CCAT1, EGFR, and miR-222-5p expression but increased CYLD expression. Loss of SOX2 also reduced the growth rate of tumor xenografts. In summary, SOX2-mediated HCC progression through an axis involving CCAT1, EGFR, and miR-222-5p upregulation and CYLD downregulation.

CircRNA_0040705 promotes the progression of hepatocellular carcinoma

“…A previous study reports that, compared with the control group, SOX2 is significantly overexpressed in HCC tissues, which are associated with the increase in TNM stage and tumor grade, and is related with the poor prognosis of patients 22 . Similarly, some other studies also report that SOX2 overexpression predicts a worse prognosis in HCC patients 23,24 . Mechanistically, knockdown of SOX2 reduces the expression levels of CCAT1, EGFR, and miR‐222‐5p, thereby inhibiting the proliferation and metastasis of HCC cells in vitro and in vivo 24 .…”

“…22 Similarly, some other studies also report that SOX2 overexpression predicts a worse prognosis in HCC patients. 23,24 Mechanistically, knockdown of SOX2 reduces the expression levels of CCAT1, EGFR, and miR-222-5p, thereby inhibiting the proliferation and metastasis of HCC cells in vitro and in vivo. 24 Interestingly, in hydroxyurea-treated HCC cells and SMMC-7721 xenografts, Slug is validated to enhance SOX2 expression, which may create a positive feedback loop and accelerate HCC progression, but it also suggests that the specific modulation of SOX2 may have a better effect in HCC treatment.…”

“…23,24 Mechanistically, knockdown of SOX2 reduces the expression levels of CCAT1, EGFR, and miR-222-5p, thereby inhibiting the proliferation and metastasis of HCC cells in vitro and in vivo. 24 Interestingly, in hydroxyurea-treated HCC cells and SMMC-7721 xenografts, Slug is validated to enhance SOX2 expression, which may create a positive feedback loop and accelerate HCC progression, but it also suggests that the specific modulation of SOX2 may have a better effect in HCC treatment. 25 In this work, SOX2 expression was observed to be down-modulated by miR-557 and indirectly up-modulated by circ_0040705, which explained the abnormal expression of SOX2 during the tumorigenesis of HCC, elucidated the upstream regulatory mechanism of SOX2, and provided a theoretical basis for the exploration of targeted therapy of SOX2.…”

Advance of SOX Transcription Factors in Hepatocellular Carcinoma: From Role, Tumor Immune Relevance to Targeted Therapy

“…SOX2, as a transcriptionally regulatory center of self-renewal in embryonic stem cells, plays a core role in reprograming adult somatic cells into a pluripotent stem cell-like state [ 35 , 36 ]. Furthermore, studies showed that SOX2 is highly expressed in HCC, and its overexpression is correlated with the poor survival of patients with HCC [ 37 , 38 ]. Consequently, the cancer-promoting effect performed by SOX2 in HCC is likely to be mainly attributable to its ability to control the stemness of HCC cells.…”

“…Consistent with this, SOX2, as a key regulator of liver CSCs, also induces the EMT process in HCC [ 37 , 46 ]. Additionally, SOX2 also involves other mechanisms to contribute to the HCC development, including mediating p38a-ROS-induced suppression of hepatocarcinogenesis and activating the CCAT1/EGFR/miR-222-5p/CYLD signal axis to promote HCC progression [ 38 , 47 ].…”