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Kharin L , Bychkov I , Karnaukhov N , Voloshin M , Fazliyeva R , Deneka A , Frantsiyants E , Kit O , Golemis E , Boumber Y
Prognostic role and biologic features of Musashi-2 expression in colon polyps and during colorectal cancer progression
PLoS One. 2021 ;16(7) :e0252132
PMID: 34237057    PMCID: PMC8266110   
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BACKGROUND: The RNA-binding protein Musashi-2 (MSI2) controls the translation of proteins that support stem cell identity and lineage determination and is associated with progression in some cancers. We assessed MSI2 as potential clinical biomarker in colorectal cancer (CRC) and tubulovillous adenoma (TA) of colon mucosa. METHODS: We assessed 125 patients, of whom 20 had polyps of the colon (TAs), and 105 had CRC. Among 105 patients with CRC, 45 had stages I-III; among metastatic CRC (mCRC) patients, 31 had synchronous and 29 metachronous liver metastases. We used immunohistochemistry to measure MSI2 expression in matching specimens of normal tissue versus TAs, primary CRC tumors, and metastases, correlating expression to clinical outcomes. We analyzed the biological effects of depleting MSI2 expression in human CRC cells. RESULTS: MSI2 expression was significantly elevated in polyps versus primary tissue, and further significantly elevated in primary tumors and metastases. MSI2 expression correlated with decreased progression free survival (PFS) and overall survival (OS), higher tumor grade, and right-side localization (p = 0.004) of tumors. In metastases, high MSI2 expression correlated with E-cadherin expression. Knockdown of MSI2 in CRC cells suppressed proliferation, survival and clonogenic capacity, and decreased expression of TGFβ1, E-cadherin, and ZO1. CONCLUSION: Elevated expression of MSI2 is associated with pre-cancerous TAs in the colonic mucosa, suggesting it is an early event in transformation. MSI2 expression is further elevated during CRC progression, and associated with poor prognosis. Depletion of MSI2 reduces CRC cell growth. These data imply a causative role of MSI2 overexpression at multiple stages of CRC formation and progression.
1932-6203 Kharin, Leonid Orcid: 0000-0002-9177-4970 Bychkov, Igor Orcid: 0000-0002-9275-5210 Karnaukhov, Nikolay Voloshin, Mark Orcid: 0000-0002-2302-3542 Fazliyeva, Rushaniya Deneka, Alexander Frantsiyants, Elena Kit, Oleg Golemis, Erica Boumber, Yanis R01 CA218802/CA/NCI NIH HHS/United States R21 CA223394/CA/NCI NIH HHS/United States R01 DK108195/DK/NIDDK NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States R21 CA228187/CA/NCI NIH HHS/United States Journal Article PLoS One. 2021 Jul 8;16(7):e0252132. doi: 10.1371/journal.pone.0252132. eCollection 2021.