Mitofusin-2 modulates the epithelial to mesenchymal transition in thyroid cancer progression

Abstract

Here, we investigated the potential roles of Mitofusin-2 (MFN2) in thyroid cancer progression. MFN2 regulates mitochondrial fusion/division in cells and plays an important role in various aspects of cell metabolism. MFN2 might involve in cell cycle regulation, apoptosis, and differentiation, and it might play a role as a tumor suppressor in carcinogenesis. We evaluated the prognostic impacts of MFN2 expression in thyroid cancer by analyzing TCGA data. In vitro and in vivo, MFN2 was knocked out using CRISPR/Cas9 or siRNA, and MFN2 was stably overexpressed in two thyroid cancer cell lines (Cal62 and HTH83). TCGA analysis revealed that MFN2 expression was lower in thyroid cancer than in normal tissues and significantly associated with a degree of differentiation, RAS mutations, and less lymph node metastasis. MFN2 expression was significantly correlated with cell adhesion molecules and epithelial to mesenchymal transition (EMT) in a gene-set enrichment assay. MFN2 knock-out (KO) in Cal62 and HTH83 cells using CRISPR/Cas9 or siRNA significantly promoted cell migration and invasion in vitro. The same trends were observed in MFN2 KO mouse embryonic fibroblasts (MEFs) compared to those in the controls (MFN2 WT MEFs). Conversely, MFN2 overexpression in cancer cell lines greatly inhibited cell migration and invasion. However, there was no difference in colony formation and proliferation in Cal62 and HTH83 cells after modulating MFN2, although there were significant differences between MFN KO and WT MEFs. EMT-associated protein expression was induced after MFN2 KO in both cancer cell lines. The mechanistic results suggest that MFN2 might modulate EMT through inducing the AKT signaling pathway. EMT-associated changes in protein expression were also confirmed by modulating MFN2 in xenograft tumors. Thus, MFN2 acts as a tumor suppressor in thyroid cancer progression and metastasis by modulating EMT.

Mitochondrial Dynamics Mediated by DRP1 and MFN2 Contributes to Cisplatin Chemoresistance in Human Ovarian Cancer SKOV3 cells

“…8 ). The role of mitochondrial dynamics mediated by DRP1 and MFN2 in migration of ovarian cancer cells is consistent with the previous studies 47 , 48 . It was reported that mitochondrial fission regulated the migration of malignant oncocytic thyroid tumor cells, breast cancer cells and lung cancer cells 49 - 51 .…”

Differential co-expression network analysis with DCoNA reveals isomiR targeting aberrations in prostate cancer

“…The direct interaction between miR-93 and 3 -UTR of FBXO31 was experimentally validated in several breast cancer cell lines by Manne et al (2017) . Another prostate cancer-specific target of miR-93, MFN2, was shown to suppress breast and thyroid cancer progression through AKT signaling ( Xu et al , 2017 ; You et al , 2021 ). The direct binding of miR-93 to 3 -UTR of MFN2 was also experimentally validated with luciferase reporter assays ( Feng et al , 2019 ; Zhang et al , 2021 ).…”

Differential co-expression network analysis with DCoNA reveals isomiR targeting aberrations in prostate cancer

“…The direct interaction between miR-93 and 3’-UTR of FBXO31 was experimentally validated in several breast cancer cell lines by Manne et al [44]. Another prostate cancer-specific target of miR-93, MFN2, was shown to suppress breast and thyroid cancer progression through AKT signaling [45, 46]. The direct binding of miR-93 to 3’-UTR of MFN2 was also experimentally validated with luciferase reporter assays [47, 48].…”