Prognostic role and biologic features of Musashi-2 expression in colon polyps and during colorectal cancer progression

Abstract

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.

Prognostic value of Musashi 2 (MSI2) in cancer patients: A systematic review and meta-analysis

“…The articles included in this study were mainly from China ( 19 , 21 – 30 , 32 – 34 , 36 ), and the rest were from Russia ( 16 , 20 ), Italy ( 40 ), Egypt ( 31 ), Germany ( 35 ) and the UK ( 37 ), and were published from 2011 to 2022. The types of cancers in the enrolled studies were OC ( 19 ), NSCLC ( 20 ), CRC ( 16 , 21 , 26 , 28 ), cervical cancer (CC) ( 22 , 25 ), pancreatic cancer (PC) ( 23 , 34 ), hepatocellular carcinoma (HCC) ( 24 , 33 ), oral squamous cells carcinoma (OSCC) ( 40 ), esophageal squamous cell carcinoma (ESCC) ( 27 ), acute lymphoblastic leukemia (ALL) ( 29 , 36 ), gastric carcinomas (GC) ( 30 ), and acute myeloid leukemia (AML) ( 31 , 32 , 35 , 37 ). The expression levels of MSI2 were detected either by IHC ( 16 , 19 – 26 , 28 , 33 , 34 , 37 , 40 ) or by qRT-PCR ( 27 , 29 – 32 , 35 , 36 ).…”

“…The characteristics of the included studies are summarized in Table 1. The articles included in this study were mainly from China (19, 21-30, 32-34, 36), and the rest were from Russia (16,20), Italy (40), Egypt (31), Germany (35) and the UK (37), and were published from 2011 to 2022. The types of cancers in the enrolled studies were OC (19), NSCLC (20), CRC (16,21,26,28),…”

“…Moreover, TGFb/Smad signaling pathway is involved in cell proliferation, differentiation, apoptosis, adhesion, invasion and cell microenvironment (8,12). In addition, multiple other studies also showed that MSI2 protein maintains cancer stem cell populations and regulates cancer invasion, metastasis and development of more aggressive cancer phenotypes, including drug resistance (8,(13)(14)(15)(16)(17)(18). Thus, MSI2 seems to be a potential prognostic biomarker and therapeutic target for cancer patients.…”

“…MSI2 has been proved to be significantly up-regulated in various cancers, such as ovarian carcinoma (OC) ( 19 ), non-small cell lung cancer (NSCLC) ( 20 ), colorectal cancer (CRC) ( 21 ), cervical cancer (CC) ( 16 ), et al. Moreover, excessive MSI2 expression is associated with poor prognosis in numerous solid tumors as well as in hematological malignancies ( 9 , 15 , 19 – 39 ), but the results are controversial ( 16 , 32 , 35 , 36 , 40 , 41 ).…”

“…MSI2 has been proved to be significantly up-regulated in various cancers, such as ovarian carcinoma (OC) ( 19 ), non-small cell lung cancer (NSCLC) ( 20 ), colorectal cancer (CRC) ( 21 ), cervical cancer (CC) ( 16 ), et al. Moreover, excessive MSI2 expression is associated with poor prognosis in numerous solid tumors as well as in hematological malignancies ( 9 , 15 , 19 – 39 ), but the results are controversial ( 16 , 32 , 35 , 36 , 40 , 41 ). Hence, we carried out this meta-analysis to further analyze the prognostic value of MSI2, so as to provide a theoretical basis for the prognosis and treatment of patients with cancer.…”