WSB2 as a target of Hedgehog signaling promoted the malignant biological behavior of Xuanwei lung cancer through regulating Wnt/β-catenin signaling

Abstract

Background: Lung cancer represents the most leading causes of cancer-related deaths worldwide, especially in Xuanwei in eastern Yunnan province, China. WD repeat and SOCS box containing protein (WSB) has been reported to participate in the carcinogenesis of lung cancer. However, there is no report about the role of WSB2 in the carcinogenesis and development of lung cancer in Xuanwei. Here, we investigated the functional role of WSB2 in Xuanwei lung cancer and uncovered its underlying molecular mechanisms. Methods: The expression of WSB2 in lung cancer cell lines and tissues were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Western blotting was used to determine the protein levels of WSB2, E-cadherin, N-cadherin, vimentin, c-Myc and β-catenin in lung cancer cells. Cell viability was detected using 3-(4,5-diethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2Hetrazolium, inner salt (MTS) assay. While cell apoptosis and cell cycle distribution were quantified using flow cytometry following indicated staining. The change of cell invasion ability was detected using Transwell assay. FH535 was employed to block Wnt/β-catenin pathway. A xenograft tumor model was applied to confirm the tumor properties of WSB2 in vivo.Results: Our data showed that WSB2 was frequently up-regulated in Xuanwei lung cancer tissues and cells, when compared with paired non-cancerous tissues and normal lung epithelial cells. Knockdown of WSB2 notably reduced cell viability, cell invasion, epithelial-mesenchymal transition (EMT) process, while induced apoptotic cell death and cell cycle arrest of Xuanwei lung cancer cells. Moreover, in vivo findings also confirmed that WSB2 knockdown could effectively delay the growth of tumor. Mechanistic studies revealed that c-Myc and β-catenin were notably decreased at both protein and mRNA levels after knocking down of WSB2, while overexpression of WSB2 showed a contrary tendency. In addition, blocking Wnt/ β-catenin pathway using FH535 rescued the cancer promoting effect mediated by overexpression of WSB2. Furthermore, WSB2 activated Wnt/β-catenin pathway and accelerated the progression of lung cancer.Conclusions: WSB2 promoted the progression of lung cancer in Xuanwei by triggering Wnt/β-catenin signaling pathway.

Wnt/β-catenin signaling in the development and therapeutic resistance of non-small cell lung cancer

“…In NSCLC, β-catenin is found to be regulated at the transcriptional level, translational level, and through subcellular translocation. The mRNA expression level of CTNNB1 can be upregulated by FLVCR1-AS1 [ 100 ], LINC01006 [ 101 ], lncRNA SNHG11 [ 102 ], TET [ 103 ], eIF3a [ 104 ], WSB2 [ 105 ], CIRP [ 106 ] and miR-214 [ 107 ] (Table 2 ). LINC01006 and lncRNA SNHG11 activate the Wnt/β-catenin pathway in LUAD cells by acting as sponges for miRNAs and elevating CTNNB1 mRNA level [ 101 , 102 ].…”

“…Loss of TET reprograms Wnt/β-catenin signaling through impaired demethylation of Wnt antagonizing genes (e.g., LRP4 , CTNNBIP1 , DACT1 , and TMEM88 ) to promote the development of NSCLC [ 103 ]. eIF3a and WSB2 regulate the transcription of CTNNB1 [ 104 , 105 ] (Table 2 ). CIRP (cold-inducible RNA binding protein) regulates CTNNB1 mRNA expression level by binding its mRNA [ 106 ].…”

Disruption of WSB2-mediated NOXA Degradation Induces Synthetic Lethality to Anti-apoptotic BCL-2 Family Protein Inhibitors

“…. WSB2 has been shown to be overexpressed in several cancers (lung cancer, breast cancer, and melanoma) and promote malignant biological behavior, such as proliferation, cycle progression, and migration [11][12][13] .…”

“…WD Repeat and SOCS Box Containing 2 (WSB2), has been classified as a substate receptor for the CRL5 E3 ubiquitin ligase complex 10 . WSB2 has been shown to be overexpressed in several cancers (lung cancer, breast cancer, and melanoma) and promote malignant biological behavior, such as proliferation, cycle progression, and migration [11][12][13] .…”

“…WD Repeat and SOCS Box Containing 2 (WSB2), has been classified as a substate receptor for the CRL5 E3 ubiquitin ligase complex 10 . WSB2 has been shown to be overexpressed in several cancers (lung cancer, breast cancer, and melanoma) and promote malignant biological behavior, such as proliferation, cycle progression, and migration 11–13 . However, a lack of reported physiological substrates for the CRL5 WSB2 complex impedes recognizing WSB2 as a potentially targetable oncoprotein for therapeutic interventions.…”