MEGF6 knockdown ameliorates lenvatinib-induced muscle differentiation suppression and enhances the antitumor effect of lenvatinib on hepatocellular carcinoma.

Lenvatinib (LEN)-treated patients with hepatocellular carcinoma (HCC) are frequently accompanied by skeletal muscle loss, which is correlated with poor prognosis. Interactions between tumor and skeletal muscle may play a role in patient prognosis and tumor progression. We here demonstrated that LEN hindered proliferation and differentiation of the mouse myoblast cell line, C2C12 cells, by blocking the ERK1/2 and AKT signaling pathways. Transcriptome analysis revealed that multiple EGF-like domains 6 (Megf6) was upregulated in LEN-treated C2C12 cells. Furthermore, we observed that compared with normal adjacent tissues, MEGF6 was highly expressed in HCC tumor tissues according to the TCGA database, which suggested MEGF6-mediated interaction between tumor and skeletal muscle. The Megf6 knockdown restored the differentiation inhibition caused by LEN and ERK1/2 inhibitors; however, it had no significant impact on proliferation. Regarding mechanism, LEN increased Megf6 expression through the ERK1/2 signaling pathway, thereby resulting in myostatin expression elevation and myosin heavy chain protein expression repression. Furthermore, MEGF6 in LEN-treated C2C12 cell medium promoted tumor cell proliferation and impaired C2C12 cell differentiation when cultured with LEN-treated tumor cell medium. Clinically, patients who were accompanied by muscle mass loss and increased MEGF6 serum levels had shorter progression-free survival than those who were accompanied by muscle mass loss but no increased MEGF6 serum levels before and after LEN treatment. In conclusion, MEGF6 produced from muscle and tumor cells could impair muscle differentiation and enhance tumor proliferation. Therefore, MEGF6 is worth further investigating as a target for improving the prognosis of LEN-treated patients with HCC.