TM4SF1 Upregulates MYH9 to Activate the NOTCH Pathway to Promote Cancer Stemness and Lenvatinib Resistance in HCC

Abstract

TM4SF1, a member of the transmembrane 4 superfamily, is crucial for both healthy and malignant human tissues. The significant function of TM4SF1 in the incidence and progression of cancer has been widely recognized in recent years. Although some achievements have been made in the study of TM4SF1, the effect of TM4SF1 on cancer stemness in hepatocellular carcinoma (HCC) and its molecular basis are yet to be reported. We found through abundant in vitro and in vivo experiments which the expression of TM4SF1 was positively correlated with the progression and cancer stemness of HCC. We identified the downstream protein MYH9 of TM4SF1 and its final regulatory target NOTCH pathway using bioinformatics analysis and protein mass spectrometry. We cultivated a lenvatinib-resistant strain from HCC cells to examine the relationship between cancer stemness and tumor drug resistance. The study confirmed that TM4SF1 could regulate the NOTCH pathway by upregulating MYH9, thus promoting cancer stemness and lenvatinib resistance in HCC. This study not only provided a new idea for the pathogenesis of HCC but also confirmed that TM4SF1 might become a new intervention point to improve the clinical efficacy of lenvatinib in treating HCC.

Breast cancer malignancy is governed by regulation of the macroH2A2/TM4SF1 axis, the AKT/NF‐κB pathway, and elevated MMP13 expression

“…TM4SF1 is suggested to be a CSC membrane marker since its extracellular domain enhances CSC functions 20 . Similarly, TM4SF1 can increase cancer stemness in hepatocellular carcinoma by activating the NOTCH pathway through the upregulation of its downstream molecule MYH9 21 . Consistently, our results confirmed that sphere formation was significantly high in breast cancer cell lines with high TM4SF1 expression than that in cells with low expression.…”

“…TM4SF1 has oncogenic functions; for example, it facilitates proliferation, 13 migration, 34 angiogenesis, 16 self‐renewal ability, 20,21 and EMT, 16,35 and inhibits the apoptosis of cancer cells 36 . Our results support these findings by showing a decrease in metastatic potential and in vivo tumor growth after TM4SF1 depletion (Figure 5).…”

“…TM4SF1 has attracted considerable attention from researchers for its role in cancer stemness regulation 15,20,21 . Therefore, we examined the role of the mH2A2/TM4SF1 axis in breast cancer stem‐like properties.…”