Silencing of CMTM6 Inhibits the Proliferation and Migration of SiHa Cervical Cancer Cells by Inhibiting MAPK Signaling

Abstract

\n Background: CKLF like MARVEL transmembrane domain containing 6 (CMTM6) is an important programmed cell death 1 ligand 1 (PD-L1) regulator. CMTM6 was identified as an immune checkpoint inhibitor，that regulates tumor T cell activity in vivo and in vitro. The function of CMTM6 in cervical cancer, however, remains unclear. In addition, whether CMTM6 participates in ovarian cancer epithelial-mesenchymal transition (EMT) is unknown.Methods: Immunohistochemistry was used to detect CMTM6 expression in cervical cancer tissues and non-cancerous adjacent tissues. CMTM6 was knocked down and overexpressed, respectively, in the human SiHa cell line. Transwell and wound healing assays were used to assess cell migration and cell invasion. Western blotting was used to detect phosphorylated (p)-C-Jun N-terminal kinase (JNK)1/2, total (t)-JNK1/2, p-p38, t-p38, and EMT-related protein levels in Siha cells. In vivo lung transplantation tumor models were used to determine if CMTM6 upregulation in ovarian cancer cells could promote metastasis.Results: CMTM6 showed higher expression in human ovarian cancer tissues than in adjacent non-cancerous tissues. In vitro assays showed that CMTM6 promoted ovarian cancer cell invasion, migration, proliferation, and EMT via MAPK JNK/p38 signaling pathway activation. Stimulating CMTM6-overexpressing cells with MAPK JNK/p38 signaling antagonists reduced SiHa cell metastasis, invasion, proliferation and EMT. In a mouse model of lung metastasis, CMTM6 increased the metastasis of ovarian cancer. Conclusion: CMTM6 activates MAPK JNK/p38 signaling to enhance the EMT and metastasis of ovarian cancer cells. These results suggest CMTM6 as a molecular target for the prevention and treatment of ovarian cancer metastasis.