According to recently released data, there would be 19.29 million new cancer cases and 9.96 million deaths worldwide in 2020, which remains a global and growing public health problem (1). Although targeted therapy and comprehensive treatment for cancers have made remarkable progress, the therapeutic effect of most tumors is still unsatisfactory (2). The main reason is the lack of effective methods for prognosis monitoring of cancer patients (3). Thus, identification of new biomarkers with the potential to predict cancer progression and prognosis will bring new hope to cancer patients.

Posttranscriptional regulation is known to control gene expression and cell behavior (4). Accumulating evidence indicates that aberrant expression and dysfunction of RNA-binding proteins (RBPs) as posttranscriptional regulators are associated with initiation, progression, and chemoresistance of various types of tumors (5, 6). The RBP Musashi-2 (MSI2) has been characterized as a cancer-driver gene in some cancers (7). It binds and regulates the mRNA stability and translation of proteins operating in vital oncogenic signaling pathways, including NUMB/Notch, PTEN/Akt/mTOR, TGFβ/SMAD, MYC, cMET, and others (7, 8). In pancreatic cancer, Sheng et al. revealed that Msi2 promotes the occurrence and development of pancreatic cancer by downregulating Numb protein that can regulate various carcinogenic signaling pathways, including Notch, p53 and Hedgehog pathways (9). Wang et al. found that Msi2 can inhibit tumor suppressor gene PTEN and activate PDK/Akt/mTORC1 signal pathway to cause tumor (10). Jiang et al. showed that Msi2 expression regulates epithelial to mesenchymal transition (EMT) by activating transcription factors Snail and TGFβR1/Smad3 signaling, which is related to chemoresistency of glioblastoma (11). Moreover, TGFβ/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, 13–18). 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). 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.

MSI-2 has been shown to be involved in numerous solid and blood malignancies, and its expression is higher than in normal tissues and correlated with prognosis. However, its prognostic role in patients with cancer is inconsistent and unclear. Thus, we reviewed published literature and conducted a meta-analysis to evaluate the association between MSI2 expression and the risk of cancer mortality and relapse. Twenty-one studies including 2640 patients were included in the meta-analysis. The results demonstrated that high MSI2 expression was significantly associated with poor prognosis, with results of poor OS (HR = 1.84, 95% CI: 1.66-2.05, P < 0.001), and poor DFS (HR = 1.73, 95% CI: 1.35-2.22, P < 0.001). In addition, the association remained significant in subgroups of OS based on cancer type, detection method, sample size and analysis method. Moreover, sensitivity analysis and publication bias showed that the results were stable and reliable. Furthermore, MSI2 positive expression was associated with certain phenotypes of tumor aggressiveness. Thus, increased MSI2 expression was associated with poor survival.

The evolutionarily conserved translation regulatory protein MSI2 is a member of the Musashi family of RBP (20). It regulates mRNA translation of many intracellular targets and maintains the properties of stem cells, thereby controlling cell proliferation and differentiation (24, 44). Thus, it is widely expressed in various tumors, and the level of expression is associated with poor prognosis of the disease (8, 39). Moreover, MSI2 was identified as a metastatic driver that supported the protein expression associated with epithelial-mesenchymal transition, including E-cadherin, the tight junction protein ZO1, the cytokine TGFβ1, the small mothers against decapentaplegic homolog 3, and the zinc finger proteins SNAI1 and SNAI2 and down-regulated expression of properties-related proteins, including claudin (claudin 3, claudin 5 and claudin 7) (16, 45). Furthermore, MSI2 plays an important role in drug resistance (11, 17, 18, 46, 47). For example, increased MSI2 expression enhances resistance to epidermal growth factor receptor tyrosine kinase inhibitors that are effective in patients with NSCLC harboring EGFR mutations (17).

Based on the fact that high expression of MSI2 can predict poor prognosis in cancer patients, and the relevant regulatory mechanisms of MSI2 in tumors, therapy targeting MSI2 may have considerable potential. In addition, small molecule inhibitors of MSI2 have been shown to be effective in vivo or in vitro. Lan et al. found that Gn, a natural inhibitor of MSI1, can similarly disrupt the binding of MSI2 to Numb RNA, like MSI1, so it is considered a dual inhibitor of MSI1 and MSI2 (48). Furthermore, the use of MSI1/MSI2 dual inhibitors such as Gn in colorectal patients with MSI overexpression can achieve better efficacy (49). In addition, Lan et al. also found that Aza-9, a derivative of secondary metabolites from Aspergillus nidulans, is a dual Msi1/2 inhibitor that can inhibit MSI2-RNA interaction in cells (50). Moreover, Aza-9-liposome inhibits proliferation, induces apoptosis and autophagy, and down-regulates Notch and Wnt signaling in colon cancer cell lines (50). Wang et al. confirmed that the small compound largazole can bind to MSI2 and may be a potential MSI2 inhibitor (51). Largazole significantly reduces MSI2 protein and mRNA levels and inhibits its downstream mammalian rapamycin signaling pathway targets (51). Largazole also inhibits proliferation and induces apoptosis in NSCLC and chronic myeloid leukemia cells (51). Thus, the MSI2 inhibitor largazole is promising as a treatment for these malignancies. Overall, the development of MSI2 inhibitors is still in the early stage, and the development of effective and highly specific MSI2 inhibitors will provide a new strategy for precise targeted therapy of tumors (8).

Although this meta-analysis comprehensively assessed the prognostic value of MSI2 expression in cancer, some limitations should be considered. First, most of the patients included in this study were from China, which to some extent affected the applicability of the results. Second, this study only included articles in Chinese and English, missing important studies published in other languages, which resulted in a certain language bias. Third, the expression level of MSI2 was not detected by a unified method, and its grouping criteria did not adopt a consistent cut-off value, which might have some effect on the results. Fourth, several HRs were extracted from the survival curves, rather than directly obtained from the article, which can cause bias.

In conclusion, the present meta-analysis demonstrated that high MSI2 expression was significantly associated with poor prognosis in various cancer patients. Thus, MSI2 can be used as a great biomarker for the prognosis of various cancers, and therapy targeting MSI2 is worthy of further study.

The data supporting this meta-analysis are from previously reported studies and datasets, which have been cited. The processed data are available within the article.

Concept and design: LJ and CZ. Literature search and extracting of data: SX, JX, JW and CZ. Analyzing and interpretation of data: XF and CZ. Drafting of the manuscript: LJ. Critical revision of the manuscript: LJ and CZ. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. All authors contributed to the article and approved the submitted version.

This work was supported by Taizhou People’s Hospital Medical Innovation Team Foundation (CXTDA201901) and Taizhou People’s Hospital Mandatory Project (ZL201929, ZL202020 and ZL202029).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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