Ubiquitin-associated protein 2 like (UBAP2L) enhances growth and metastasis of gastric cancer cells

Abstract

Ubiquitin-proteasome pathway has emerged as therapeutic targets for cancer. GEPIA database analysis showed that the expression of ubiquitin-associated protein 2 like (UBAP2L) in gastric cancer specimens was significantly higher than that in non-tumor tissue, and its high expression is associated with poor survival of gastric cancer patients. This study aims to investigate the role of UBAP2L in gastric cancer. Real-time PCR and western blot results showed that UBAP2L expression was upregulated in gastric cancer cell lines. Loss- and gain-of-function experiments demonstrated that silencing of UBAP2L inhibited proliferation, migration and invasion, and induced apoptosis of gastric cancer cells, and overexpression of UBAP2L played opposite roles. Nude mice inoculated with UBAP2L-silenced gastric cancer cells generated smaller xenografted tumors in vivo . Furthermore, UBAP2L activated Wnt/β-catenin signaling – the accumulation of nuclear β-catenin and the expression of its downstream targets (cyclin D1, AXIN-2 and c-MYC) was facilitated, whereas knockdown of UBAP2L deactivated this signaling. The tumor-suppressing effect of UBAP2L silencing was abolished by forced activation of β-catenin S33A . UBAP2L has been confirmed as a novel and direct target of miR-148b-3p. The anti-tumor effect of miR-148b-3p was partly reversed by UBAP2L overexpression. The expression of miR-148b-3p was negatively correlated with that of UBAP2L in gastric cancer samples. Overall, our study indicates that UBAP2L is required to maintain malignant behavior of gastric cancer cells, which involves the activation of Wnt/β-catenin signaling pathway. We propose UBAP2L as a potential therapeutic target against gastric cancer.

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“…The membranes were and then incubated with secondary antibodies. The protein bands were visualized using an ECL reagent (GE Healthcare) [ 18 ].…”

Systematic Analysis of Stress Granule Regulators-Associated Molecular Subtypes Predicts Drug Response, Immune Response, and Prognosis in Non-Small Cell Lung Cancer

“…Also, we revealed UBAP2L was significantly up-regulated in NSCLC. UBAP2L has been shown to be overexpressed in several tumors, such as liver carcinoma ( Wang et al, 2017 ), breast cancer ( He et al, 2018 ) and gastric cancer ( Lin et al, 2021 ). Also, previous studies showed UBAP2L was amplified in LUAD and is critical for tumor metastasis ( Aucagne et al, 2017 ).…”

Ubiquitin Binding Protein 2-Like (UBAP2L): is it so NICE After All?

“…First, in non-small cell lung cancer (NSCLC), miR-19a-3p directly inhibits UBAP2L, resulting in similar phenotypes as those observed upon UBAP2L downregulation, mainly inhibition of cell proliferation, migration and invasion ( Pan et al, 2020 ). Similarly, UBAP2L was silenced by miR-148b-3p in gastric cancer cells leading to the same phenotypes as in NSCLC ( Lin et al, 2021 ). Interestingly, the UBAP2L ortholog PQN-59 stabilizes several miRNAs involved in various cellular functions and interacts with RNA metabolism, transcription and translation cellular components similarly to UBAP2L, highlighting the importance of this protein in RNA regulation ( Carlston et al, 2021 ).…”

“…Consistently, cells lacking UBAP2L harbor increased epithelial (E-cadherin, CK-18) and decreased mesenchymal markers (N-cadherin, vimentin) ( Ye et al, 2017 ), highlighting UBAP2L’s crucial role in regulating the metastatic potential of cancer cells. In addition to HCC, the promotion of EMT by UBAP2L has also been reported in prostate, lung and gastric cancers ( Li and Huang, 2014 ; Aucagne et al, 2017 ; Lin et al, 2021 ). Complementary studies verified these conclusions in vivo where inhibition of UBAP2L led to defective cancer invasion in xenografts ( Guan et al, 2021 ).…”

“…For example, components of the Wnt/β-catenin signaling which is a highly conserved pathway regulating fundamental developmental processes, has been frequently observed to be mutated in cancer ( Nusse and Clevers, 2017 ). Not surprisingly, UBAP2L has been proposed to activate the Wnt/β-catenin signaling cascade in gastric cancer cells, leading to the expression of downstream pathway targets, known to be implicated in tumorigenesis and metastasis ( Yook et al, 2006 ; Liu et al, 2010 ; Damsky et al, 2011 ; Lin et al, 2021 ). However, the precise molecular mechanisms driving UBAP2L’s oncogenic potential are not yet defined.…”