Musashi2 promotes the progression of pancreatic cancer through a novel ISYNA1‐p21/ZEB‐1 pathway

Abstract

Our previous studies found overexpression of Musashi2 (MSI2) conduced to the progression and chemoresistance of pancreatic cancer (PC) by negative regulation of Numb and wild type p53 (wtp53). Now, we further investigated the novel signalling involved with MSI2 in PC. We identified inositol‐3‐phosphate synthase 1 (ISYNA1) as a novel tumour suppressor regulated by MSI2. High MSI2 and low ISYNA1 expression were prevalently observed in 91 PC tissues. ISYNA1 expression was negatively correlated with MSI2 expression, T stage, vascular permeation and poor prognosis in PC patients. What's more, patients expressed high MSI2 and low ISYNA1 level had a significant worse prognosis. And in wtp53 Capan‐2 and SW1990 cells, ISYNA1 was downregulated by p53 silencing. ISYNA1 silencing promoted cell proliferation and cell cycle by inhibiting p21 and enhanced cell migration and invasion by upregulating ZEB‐1. However, MSI2 silencing upregulated ISYNA1 and p21 but downregulated ZEB‐1, which can be rescued by ISYNA1 silencing. Moreover, reduction of cell migration and invasion resulting from MSI2 silencing was significantly reversed by ISYNA1 silencing. In summary, MSI2 facilitates the development of PC through a novel ISYNA1‐p21/ZEB‐1 pathway, which provides new gene target therapy for PC.

Musashi-2 contributes to myotonic dystrophy muscle dysfunction by promoting excessive autophagy through miR-7 biogenesis repression

“…Additionally, we quantified TGFBR1 levels, as it was demonstrated to be directly regulated by MSI2 24 and also P21 , which, in contrast to TGFBR1 , is inhibited by MSI2. 25 TGFBR1 levels dropped (near 40%), and P21 levels, however, did not significantly change ( Figure 2 B). MSI2 silencing was also assessed at the level of the strong myotubes fusion phenotype described for TDMs, which we previously showed that miR-7 overexpression was sufficient to improve.…”

ISYNA1: An Immunomodulatory-Related Prognostic Biomarker in Colon Adenocarcinoma and Pan-Cancer

“…For example, ISYNA1 was observed as highly expressed in BLCA, regulating the proliferation and apoptosis of BLCA cells ( Guo et al, 2019 ). In pancreatic cancer, the ISYNA1-p21/ZEB-1 pathway could contribute to tumor progression ( Zhou L et al, 2020 ).…”

SLC5A3-Dependent Myo-inositol Auxotrophy in Acute Myeloid Leukemia

“…For example, the inositol hexakisphosphate kinase 1 (IP6K1) has been found in the nucleus where it acts directly to maintain transcription of ISYNA1 and prevent DNA hypermethylation (65). In addition, prior studies have shown that Musashi2, a known oncogene, regulates ISYNA1 expression in the context of cancer (66). The tumor suppressor p53 has also been shown to directly regulate the ISYNA1 promoter (67).…”