Positive feedback loop of IGF2BP3/IL6ST/STAT3 facilitates malignant progression in colorectal cancer

Colorectal adenocarcinoma (COAD) accounts for approximately 90% of colorectal cancer (CRC) cases and is the most common histological subtype of CRC. COAD, a malignancy associated with high morbidity and mortality, remains a topic of debate, with its underlying molecular mechanisms requiring further investigation. Differential analysis and survival analysis were used to evaluate IGF2BP3 expression and prognosis. CCK8, colony formation, and the impact of IGF2BP3 on tumor malignancy were analyzed in transwell apples. GEO data were used to screen potential substrates modified by IGF2BP3. Western blotting, RT-qPCR, and RIP-qPCR were used to validate the predictions. Animal models were constructed to validate the tumor-promoting effects of IGF2BP3. IGF2BP3 is highly expressed in COAD and correlates with poor patient prognosis. IGF2BP3 activates the JAK2/STAT3 signaling pathway by recognizing m6A-modified IL6ST mRNA. STAT3 transcriptionally regulates IGF2BP3. Importantly, IGF2BP3 enhances the malignant phenotype of COAD both in vivo and in vitro. In this study, we found IGF2BP3 promotes tumor progression in an m6a manner. Mechanistically, IGF2BP3 recognizes and stabilizes IL6ST, activating the JAK2/STAT3 pathway. In turn, STAT3 transcriptionally activates IGF2BP3, forming an IGF2BP3-STAT3 positive feedback loop that promotes tumorigenesis.