m(6)A-modified lncRNA MIAT promotes anoikis resistance and peritoneal metastasis of colorectal cancer through miR-181a-5p/MCL1 signaling axis.

Colorectal cancer peritoneal metastasis (CRCPM) represents a highly aggressive clinical condition associated with limited therapeutic options and poor prognosis. Anoikis resistance, a specialized form of apoptosis induced by loss of cell-matrix interactions, is essential for tumor cell survival during peritoneal dissemination.

However, the molecular mechanisms underlying anoikis resistance in CRCPM remain poorly understood. Differentially expressed lncRNAs associated with CRCPM were identified using microarray analysis and validated in clinical specimens. Gain- and loss-of-function assays were performed to evaluate the biological role of MIAT in colorectal cancer (CRC) cells, patient-derived organoids, and in vivo models. RNA pull-down, luciferase reporter, and RNA immunoprecipitation (RIP) assays were conducted to investigate the ceRNA mechanism.

Methylated RNA immunoprecipitation (MeRIP) and RNA stability assays were used to assess m6A modification and its regulatory effects on MIAT. MIAT was significantly upregulated in CRCPM tissues and anoikis-resistant CRC cells and was associated with poor prognosis. Functional assays demonstrated that MIAT silencing suppressed CRC cell proliferation, migration, invasion, and anoikis resistance in vitro and inhibited tumor growth and peritoneal metastasis in vivo. Mechanistically, MIAT acted as a competing endogenous RNA by sponging miR-181a-5p, thereby upregulating the anti-apoptotic protein MCL1.

Furthermore, MIAT stability was enhanced by METTL3-mediated m6A modification in an IGF2BP2-dependent manner.

These findings identify a novel m6A-MIAT/miR-181a-5p/MCL1 signaling axis that promotes anoikis resistance and peritoneal metastasis in CRC.

This study provides mechanistic insights into CRCPM progression and highlights MIAT as a potential prognostic biomarker and therapeutic target.