Long noncoding RNA Meg3 sponges miR-708 to inhibit intestinal tumorigenesis via SOCS3-repressed cancer stem cells growth

• Published in: Cell death & disease 2021-12, Vol.13 (1), p.25-13, Article 25
• Main Authors: Zhang, Shuo, Ji, Wei-Wei, Wei, Wei, Zhan, Li-Xing, Huang, Xuan
• Format: Article
• Language: English
• Subjects: 13; 13/100; 13/106; 13/109; 38; 38/47; 38/77; 38/90; 631/67/71; 692/308/2171; 82; 82/51; Adenomatous polyposis coli; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cancer; Carcinogenesis; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Proliferation; Colorectal cancer; Colorectal carcinoma; Disease Models, Animal; Female; Humans; Immunology; Immunoprecipitation; Intestine; Life Sciences; Male; Mice; MicroRNAs - metabolism; Neoplastic Stem Cells - metabolism; Organoids; RNA, Long Noncoding - metabolism; Stat3 protein; Stem cell transplantation; Stem cells; Suppressor of Cytokine Signaling 3 Protein - metabolism; Tumor suppressor genes; Tumorigenesis
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04470-5

Background Colorectal cancer (CRC) remains the most common gastrointestinal cancer and a leading cause of cancer deaths worldwide, with most showing pathologies indicating the malignant transformation of early stage intestinal stem cells. The long non-coding RNA Meg3 , which functions as a tumor suppressor, has been reported to be abnormal in multiple tumorigenesis events; however, the underlying mechanism by which Meg3 contributes to the malignant proliferation of colonic stem cells remains unclear. Methods We analyzed the expression levels of Meg3 , miR-708 , and SOCS3 in samples from Apc loss-of-function ( Apc min ) mice and patients with CRC, particularly in colonic crypt cells. Apc min mice and AMO/DSS-induced mice model (in vivo) and organoid culture system (in vitro) were used to explore the effect of the Meg3 / miR-708 /SOCS3 axis on tumorigenesis in the colon. In vitro, we performed RNApull-down, RNA immunoprecipitation, and luciferase reporter assays using DLD1 and RKO cell lines. Findings The Meg3 / miR-708 /SOCS3 signaling axis plays a critical role in the early stage of CRC development. Our data showed Meg3 levels negatively correlate with miR-708 levels both in clinical samples and in the Apc min mouse model, which indicated that Meg3 acts as a competitive endogenous RNA (ceRNA) of miR-708 . Then, miR-708 served as an oncogene, inducing neoplasia in both Apc min mice and cultured colonic organoids. Put together, miR-708 appears to promote malignant proliferation of colonic stem cells by targeting SOCS3/STAT3 signaling. Interpretation These data revealed that Meg3 sponges miR-708 to inhibit CRC development via SOCS3-mediated repression of the malignant proliferation of colonic stem cells. The Meg3 / miR-708 /SOCS3 signaling axis provides potential targets for the diagnosis and treatment of CRC, particularly early stage CRC.