N6-methyladenosine Reader IGF2BP2-modified HMMR Promotes Non-small Cell Lung Cancer Metastasis via Interaction with MAP4K4.

Abstract

Globally, lung cancer represents the leading cause of cancer-related mortality, with 85% of cases attributable to non-small cell lung cancer (NSCLC). Metastatic progression remains a major challenge in treating advanced lung cancer, resulting in a dismal five-year survival rate of 20-30%. Hyaluronan mediated motility receptor (HMMR) has been identified as a novel oncogene in NSCLC. However, its exact role and mechanisms in NSCLC and metastasis are yet to be fully understood. Elevated mRNA and protein levels of HMMR were observed in human NSCLC tumors in comparison with normal adjacent tissues. Increased HMMR expression was associated with poorer prognosis, with multivariate Cox regression analysis also identifying it as an independent prognostic factor. HMMR knockdown inhibited tumor cell migration and invasion, while its overexpression enhanced these processes. Mechanistically, HMMR promotes tumor metastasis by binding to mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which activates the p-JNK/p-c-JUN/MMP1 signaling cascade. The effects of HMMR overexpression on metastatic potential and JNK signaling were confirmed by MAP4K4 knockdown or GNE-495 treatment. Additionally, insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) was found to bind to the N⁶-methyladenosine (m⁶A) site of HMMR, increasing mRNA stability and HMMR expression levels. In a mouse model, the MAP4K4 inhibitor GNE-495 successfully suppressed lung metastasis induced by HMMR overexpression. These results offer valuable insights into HMMR's biological functions while suggesting potential avenues for novel treatments.