LINC00162 silencing enhances sorafenib sensitivity and inhibits thyroid cancer cells progression through modulation of MAPK signaling and apoptosis

Abstract Many studies have reported the aberrant expression of lncRNAs and indicated their role in cancer progression and drug resistance across various cancers. In this study, we aimed to evaluate the effect of LINC00162 lncRNA on the chemosensitivity of thyroid cancer cells, both individually and in combination with sorafenib, on various biological processes. In this regard, we conducted our experiments in several groups: (1) LINC00162 siRNA-transfected cells, (2) Sorafenib-treated cells, (3) Cells that received both siRNA transfection and sorafenib treatment (4) Control group. MTT assay results revealed that siRNA-mediated silencing of LINC00162 reduced the viability of the B-CPAP thyroid cancer cells and increased the sensitivity of these cells to sorafenib by reducing its IC50. Flow cytometry analysis of apoptosis and cell cycle progression indicated that LINC00162 silencing induced apoptosis and Sub-G1 cell cycle arrest, while its combination with sorafenib significantly increased the apoptosis rate and also arrested cells in the G2-M phase in addition to the Sub-G1 phase. This combination treatment increased the expression of apoptosis-related genes BAX, CASP3, CASP9 while decreasing BCL2 expression. Additionally, significant inhibition of the cell-cycle related genes MYC and Cyclin D and upregulation of TP53 were observed following combination treatment. Furthermore, the combination therapy reduced the migration of B-CPAP cells through the downregulation of MMP-3 and MMP-9. Colony sizes and numbers also decreased following siRNA-mediated silencing of LINC00162 and sorafenib treatment. qRT-PCR analysis of stemness-related genes, including NANOG, SOX2, CD44, and CD133 confirmed the findings of the colony formation assay. To understand the underlying mechanisms of LINC00162 lncRNA in thyroid cancer progression, we evaluated the expression of MAPK pathway genes. Our findings indicated that LINC00162 silencing, in combination with sorafenib, reduced the expression of MAPK, KRAS, and RAF genes. From our findings, we can conclude that LINC00162 silencing, both individually and combined with sorafenib, reduced the progression and viability of thyroid cancer cells through modulating genes involved in key pathways and could be considered a new therapeutic approach for the treatment of papillary thyroid cancer (PTC).