TPX2‐p53‐GLIPR1 regulatory circuitry in cell proliferation, invasion, and tumor growth of bladder cancer

Abstract

The targeting protein for Xenopus kinesin-like protein 2 (TPX2) is associated with the metastasis and prognosis of bladder cancer. p53 is closely related to the progression of bladder cancer. Human glioma pathogenesis-related protein 1 (GLIPR1) is a p53 target gene with antitumor activity. This study aims to explore the interplay between TPX2, p53, and GLIPR1 and its correlation with cell proliferation, invasion, and tumor growth in bladder cancer. Here, Western blot and qRT-PCR analysis revealed that TPX2 at both mRNA and protein levels was up-regulated in bladder carcinoma tissues compared to their paired adjacent normal tissues. Additionally, tissues expressing high TPX2 level exhibited high p53 level and low GLIPR1 level. The expressions of TPX2 and p53 in non-muscle-invasive bladder cancer cells (KK47 and RT4) were lower than those in muscle-invasive bladder cancer cells (T24, 5637, and UM-UC-3), while GLIPR1 showed the converse expression pattern. Further investigation revealed that TPX2 activated the synthesis of p53; and GLIPR1 is up-regulated by wild-type (wt)-p53 but not affected by mutated p53; Additionally, GLIPR1 inhibited TPX2. These data suggested a TPX2-p53-GLIPR1 regulatory circuitry. Meanwhile, TPX2 overexpression promoted while overexpression of GLIPR1 or p53 inhibited bladder cancer growth. Interestingly, in T24 cells with mutated p53, p53 silence suppressed bladder cancer growth. This study identified a novel TPX2-p53-GLIPR1 regulatory circuitry which modulated cell proliferation, migration, invasion, and tumorigenicity of bladder cancer. Our findings provide new insight into underlying mechanisms of tumorigenesis and novel therapeutic options in bladder cancer.

GLIPR1 expression is reduced in multiple myeloma but is not a tumour suppressor in mice

“…Overexpression of GLIPR1 in prostate, bladder and lung cancer, as well as osteosarcoma cells, has been demonstrated to reduce tumour cell proliferation and/or colony formation in vitro [24,25,27,29]. In contrast, neither the overexpression of GLIPR1 in the H929 HMCL nor the re-expression of Glipr1 in the 5TGM1 murine MM cell line affected basal tumour cell proliferation or colony formation in vitro.…”

“…A reduction in GLIPR1 expression was shown to be a feature of several solid cancers, including prostate, lung and bladder cancer, as well as sarcoma [24][25][26][27]. In all cases, GLIPR1 demonstrated tumour suppressor activity in vitro [24][25][26][27][28][29], and, furthermore, GLIPR1 expression was shown to suppress prostate cancer tumour growth in vivo [30]. GLIPR1 has been found to mediate its tumour suppressor effects in prostate cancer cells through several different mechanisms [29,31,32].…”

“…GLIPR1 is a ubiquitously expressed gene that encodes a member of the cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP) superfamily with unspecified function [22,23]. A reduction in GLIPR1 expression was shown to be a feature of several solid cancers, including prostate, lung and bladder cancer, as well as sarcoma [24][25][26][27]. In all cases, GLIPR1 demonstrated tumour suppressor activity in vitro [24][25][26][27][28][29], and, furthermore, GLIPR1 expression was shown to suppress prostate cancer tumour growth in vivo [30].…”

Identification of Novel Hub Genes Through Expression Profiles Analysis in Adrenocortical Carcinoma

“…With the help of MYC, TPX2 could also cooperate with AURKA to drive the tumorigenesis of colon cancer, providing a promising therapeutic option for MYC-driven tumors by inhibition of the AURKA-TPX2 axis [37,38]. In terms of the association between TPX2 and p53, a novel regulatory circuitry of TPX2-p53-GLIPR1 was found in bladder cancer to regulate proliferation, migration, invasion, and tumorigenicity, while silencing of TPX2 could activate p53 signaling and inhibit the proliferation of breast cancer cells [39,40]. Together, these data suggest that TPX2 might be a promising target for the prediction of prognosis and therapeutic approaches in ACC and future studies concerning TPX2 in ACC should be warranted.…”

Identification of Molecular Markers Associated with Diagnosis and Prognosis in Lung Adenocarcinoma by Bioinformatics Analysis

“…In ovarian cancer, it can promote the proliferation and migration of human ovarian cancer cells by regulating PLK1 expression [39]. Except for these function, in various cancers can TPX2 also control bladder cancer cell's proliferation and invasion via TPX2-p53-GLIPR1 regulatory circuitry [40], regulate the PI3K/AKT signaling pathway to facilitate hepatocellular carcinoma [41], interactive with miRNA such as miR-485-3p [42], miR-361-5p [43], miR-335-5p [44], miR-216b [45] and so on. Zhou et al have veri ed that TPX2 can activate the epithelial-mesenchymal transition process and promote both the expression and activities of matrix metalloproteinase (MMP)2 and MMP9 in non-small cell lung cancer (NSCLC), which means TPX2 promotes the metastasis and malignant progression of NSCLC and could thus serve as a marker of poor prognosis in NSCLC [46].…”