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LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3.

ABSTRACT: The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unraveled a potentially novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2, and LoVo) with either knockdown or overexpression of LIN28B, we identified claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B. RNA immunoprecipitation revealed that LIN28B directly binds to and posttranscriptionally regulates CLDN1 mRNA. Furthermore, using in vitro assays and a potentially novel murine model of metastatic CRC, we show that LIN28B-mediated CLDN1 expression enhances collective invasion, cell migration, and metastatic liver tumor formation. Bulk RNA sequencing of the metastatic liver tumors identified NOTCH3 as a downstream effector of the LIN28B/CLDN1 axis. Additionally, genetic and pharmacologic manipulation of NOTCH3 signaling revealed that NOTCH3 was necessary for invasion and metastatic liver tumor formation. In summary, our results suggest that LIN28B promotes invasion and liver metastasis of CRC by posttranscriptionally regulating CLDN1 and activating NOTCH3 signaling. This discovery offers a promising new therapeutic option for metastatic CRC to the liver, an area where therapeutic advancements have been relatively scarce.

SUBMITTER: Sugiura K

PROVIDER: S-EPMC10443801 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3.

Sugiura Kensuke K Masuike Yasunori Y Suzuki Kensuke K Shin Alice E AE Sakai Nozomu N Matsubara Hisahiro H Otsuka Masayuki M Sims Peter A PA Lengner Christopher J CJ Rustgi Anil K AK

JCI insight 20230724 14

The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unraveled a potentially novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2, and LoVo) with either knockdown or overexpression of LIN28B, we identified claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B. RN ...[more]

PMID: 37318881

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Project description:To explore the relationship between miR-373 and the occurrence and development of colorectal cancer. Additionally, it aims to predict the potential cellular signaling pathways and regulatory mechanisms in which miR-373 may be involved and provides a theoretical basis and experimental evidence for the clinical application of miR-373 as a potential biomarker, molecular target, and prognostic indicator in colorectal cancer. Real-time quantitative PCR is used to analyze the expression of miR-373 in human colorectal cancer cell lines and normal human colonic epithelial cells. Further validation of the differential expression of miR-373 in colorectal cancer cell lines is being performed. Biological functions such as cell proliferation, invasion and apoptosis are being detected by MTT, CCK-8, transwell, cell cycle analysis, and flow cytometry experiments to verify the changes in the biological behavior of colon cancer cells after overexpression and interference of miR-373 in SW-480 cells and to explore the effects of miR-373 on cell proliferation, invasion, and apoptosis in colon cancer cells. Proteomic analysis is being conducted on proteins extracted from miR-373 overexpressing SW480 cells, and mass spectrometry is used for protein identification. GO, KEGG, and enrichment analysis are being employed to analyze the significantly differentially expressed proteins. The expression levels of pathway-related proteins are being verified using Western blot. Overexpression of miR-373 increased the invasive and metastatic ability of SW-480 cells; knockdown of miR-373 decreased the invasive and metastatic ability of SW-480 cells. However, there was no statistically significant effect on cell proliferation and apoptosis in SW-480 cells. Proteomic analysis identified 78 differentially expressed proteins based on fold change (FC) > 1.2 and P < 0.05. Annotation of differentially changed proteins revealed that the MAPK signaling pathway, PI3K-Akt signaling pathway, and FAK signaling pathway may play crucial roles in the migration and invasion of colorectal cancer. Western blot analysis showed that overexpression of miR-373 significantly increased the levels of p-ERK1/2 in SW480 cells. miR-373 may activate the ERK/MAPK signaling pathway to promote the invasion and migration of colorectal cancer cells.

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LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3.

Publications

LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3.

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