Prognostic significance of Musashi 2 (MSI2) RNA-binding protein expression in precancerous polyps and during colorectal cancer (CRC) progression.

Abstract

e16009 Background: The RNA-binding protein Musashi-2 (MSI2) controls the translation of proteins that support stem cell identity and lineage determination. Elevated expression of MSI2 plays an important role during progression, dissemination, and drug resistance in numerous solid and hematological malignancies. This study assessed MSI2 as potential clinical biomarker in colorectal cancer (CRC) and pre-malignant disorders of colon mucosa. Methods: This study included 125 patients, of whom 20 had tubulovillous adenomas (TAs) of the colon, and 105 had verified colorectal cancer. Of the 105 patients with CRC, 45 had locoregional invasion (stages I-III). The remaining 60 patients had liver metastases (mCRC), with 31 patients diagnosed with synchronous and 29 with metachronous metastases. We used immunohistochemical (IHC) approach to measure MSI2 expression in matching specimens of normal versus TA tissues, normal versus primary CRC tumor, and normal versus metastatic CRC, followed by correlative analysis in relation to clinical outcomes. In parallel, the biological effects of overexpressing or depleting MSI2 expression in human CRC cells were analyzed in vitro using qRT-PCR, western blot, proliferation and clonogenic assays. Results: MSI2 expression in patient samples was significantly elevated in TAs versus primary tissue (p < 0.002), and was further elevated in primary tumor, and in metastatic sites (p < 0.0001 versus normal tissue, p < 0.003 versus TAs). MSI2 expression positively correlated with decreased progression free survival (PFS) and overall survival (OS), lower tumor grade, and right-side localization (p = 0.004) of tumors. In vitro knockdown of MSI2 in CRC cells suppressed of proliferation, survival and clonogenic capacities of the cells. Conclusions: Elevated expression of MSI2 is associated with pre-cancerous polyps (TAs) in the colonic mucosa, indicating it is an early event in transformation. MSI2 is further elevated during, CRC progression, and associated with poor prognosis, and loss of MSI2 reduces multiple growth properties of CRC cell models. These data imply a causative role of MSI2 overexpression at multiple stages of CRC formation and progression.