WNT ligands in non-small cell lung cancer: from pathogenesis to clinical practice

Abstract

Non-small cell lung cancer (NSCLC) is the malignant tumor with the highest morbidity and leading cause of death worldwide, whereas its pathogenesis has not been fully elucidated. Although mutations in some crucial genes in WNT pathways such as β-catenin and APC are not common in NSCLC, the abnormal signal transduction of WNT pathways is still closely related to the occurrence and progression of NSCLC. WNT ligands (WNTs) are a class of secreted glycoproteins that activate WNT pathways through binding to their receptors and play important regulatory roles in embryonic development, cell differentiation, and tissue regeneration. Therefore, the abnormal expression or dysfunction of WNTs undoubtedly affects WNT pathways and thus participates in the pathogenesis of diseases. There are 19 members of human WNTs, WNT1, WNT2, WNT2b, WNT3, WNT3a, WNT4, WNT5a, WNT5b, WNT6, WNT7a, WNT7b, WNT8a, WNT8b, WNT9a, WNT9b, WNT10a, WNT10b, WNT11 and WNT16. The expression levels of WNTs, binding receptors, and activated WNT pathways are diverse in different tissue types, which endows the complexity of WNT pathways and multifarious biological effects. Although abundant studies have reported the role of WNTs in the pathogenesis of NSCLC, it still needs further study as therapeutic targets for lung cancer. This review will systematically summarize current research on human WNTs in NSCLC, from molecular pathogenesis to potential clinical practice.

Characterization of a Preclinical In Vitro Model Derived from a SMARCA4-Mutated Sinonasal Teratocarcinosarcoma

“…TCS cases with only some focal staining of nuclear β-catenin with or without CTNNB1 mutation have been described in the literature, and this may be related to the interaction of SMARCA4 with the Wnt pathway [ 19 , 21 , 25 , 50 ]. WES analysis of TCS627 did indicate a mutation in WNT7A , a factor that can activate the canonical and non-canonical Wnt pathways described as a tumor suppressor in lung cancer but also as an oncogene in ovarian, breast and brain tumors [ 51 , 52 ]. The effect of the non-synonymous WNT7A mutation on protein function in the TCS627 cell line will require further study.…”

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

“…In humans, the complexity and specificity of Wnt signaling is achieved partially through 19 Wnt ligands [ 4 ]. The aberrant expression of most Wnt ligands have been found to closely correlate to the occurrence and progression of NSCLC, and are the thus potential biomarkers and drug targets for the diagnosis, prognosis, and treatment of NSCLC [ 26 ]. Overexpression of WNT2B , WNT3A and WNT5A has been found to associate with NSCLC [ 27 , 28 ] (Table 1 ).…”

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical β-catenin pathway

“…The overall survival rate was significantly lower in non-small cell lung cancer (NSCLC) patients with high-WNT3 tumors than in those with low-WNT3 tumors [ 30 ]. Knockdown of WNT3 in human NSCLC cells suppressed cellular proliferation, invasion and metastasis, and induced apoptosis by inhibiting the canonical WNT pathway and the upregulation of WNT3 promoted cisplatin resistance [ 31 , 32 ]. WNT3 contributed to cell adhesion–mediated drug resistance (CAM-DR) of myeloma cells via the WNT/RhoA/ROCK pathway of myeloma cells in an autocrine manner [ 33 ].…”