RNA-Binding Proteins MCPIP3 and IGF2BP3 Antagonize Lung Cancer Metastasis by Reversibly Regulating METAP2 Expression...

Background/Objectives: The homeostatic imbalance between tumor metastasis-promoting genes and metastasis-suppressing genes determines the metastatic potential of lung adenocarcinoma (LUAD) cells. However, the post-transcriptional regulation mechanism mediated by RNA-binding proteins (RBPs) in maintaining the expression balance of tumor metastasis-related genes remains unclear. Methods: The expression of MCPIP3 and IGF2BP3 in human lung cancer tissues was analyzed using bioinformatics methods and validated using qRT-PCR, immunohistochemistry, and immunoblotting. In vitro cellular experiments and in vivo animal examinations were used to evaluate the effects of MCPIP3 and IGF2BP3 on metastasis. RNA sequencing, PCRarray, RNA pull-down and mass spectrometry, RNA-EMSA, RNA immunoprecipitation (RIP), mRNA stability, and luciferase assays were performed to elucidate the mechanism. Results: MCPIP3 is expressed at low levels, while IGF2BP3 is highly expressed in LUAD tissues. Lower MCPIP3 expression and higher IGF2BP3 expression in lung cancer tissues were significantly associated with poor prognosis in LUAD patients. MCPIP3 significantly inhibited the metastasis of lung cancer cells both in vitro and in vivo, whereas IGF2BP3 promoted metastasis. Mechanistically, MCPIP3 specifically bound to the stem-loop structure in the 3'UTR (untranslated region) of the METAP2 transcript and degraded its mRNA via its RNase domain. In contrast, by interacting with the common stem-loop structure, IGF2BP3 could stabilize METAP2 mRNA and promote its expression. Notably, inverse correlations were observed between the expression of MCPIP3 and IGF2BP3 and the expression of METAP2 in LUAD tissues. Conclusions: MCPIP3 and IGF2BP3 antagonistically control lung cancer cell metastasis by balancing the expression of metastasis-promoting genes through mediating mRNA stability, thereby providing potential targets for lung cancer treatment.