Silencing ZIC2 abrogates tumorigenesis and anoikis resistance of non-small cell lung cancer cells by inhibiting Src/FAK signaling

Abstract

Aberrant expression of the zinc finger protein (ZIC) family has been extensively reported to contribute to progression and metastasis in multiple human cancers. However, the functional roles and underlying mechanisms of ZIC2 in non-small cell lung cancer (NSCLC) are largely unknown. In this study, ZIC2 expression was evaluated using qRT-PCR, western blot, and immunohistochemistry, respectively. Animal experiments in vivo and functional assays in vitro were performed to investigate the role of ZIC2 in NSCLC. Luciferase assays and chromatin immunoprecipitation (ChIP) were carried out to explore the underlying target involved in the roles of ZIC2 in NSCLC.Here, we reported that ZIC2 was upregulated in NSCLC tissues, and high expression of ZIC2 predicted worse overall and progression-free survival of NSCLC patients. Silencing ZIC2 repressed tumorigenesis and reduced the anoikis resistance of NSCLC cells. Mechanical investigation further revealed that silencing ZIC2 transcriptionally inhibited Src expression and inactivated steroid receptor coactivator/focal adhesion kinase signaling, which further attenuated the anoikis resistance of NSCLC cells. Importantly, our results showed that the number of circulating tumor cells (CTCs) was positively correlated with ZIC2 expression in NSCLC patients. Collectively, our findings unravel a novel mechanism implicating ZIC2 in NSCLC, which will facilitate the development of anti-tumor strategies in NSCLC.

Identification and experimental verification of an anoikis and immune related signature in prognosis for lung adenocarcinoma

“…In non-small cell lung cancer, aberrant expression of the zinc finger protein ( ZIC ) family was associated with anoikis, and silencing ZIC2 reduced anoikis resistance in NSCLC cells. In addition, the number of circulating tumor cells and ZIC2 expression were positively correlated ( 41 ). Also, in gastric cancer, anoikis resistance interacts biologically with angiogenesis, thus promoting peritoneal metastasis of gastric cancer ( 42 ).…”

Blood-Derived Exosomal hTERT mRNA in Patients with Lung Cancer: Characterization and Correlation with Response to Therapy

“…As described in the introduction, exosome analysis has been reported as a diagnostic liquid-biopsy-based tool for lung carcinoma [ 53 , 54 , 55 ]. Most studies identifying exosomal cargo in plasma or sera derived from patients with lung carcinoma describe certain microRNA signatures as diagnostic markers [ 76 , 77 , 78 , 79 , 80 , 81 , 82 ]. All in all, the reported implication of exosomal cargo in the aggressiveness of lung cancer suggests that the inhibition of exosome formation and release may be a potential new strategy for the treatment of lung cancer [ 82 ].…”

Anoikis-Associated Lung Cancer Metastasis: Mechanisms and Therapies

“…Some regulators counteract anoikis through Src, including zinc finger protein 2 (ZIC2) and growth factor receptors. ZIC2 promoted tumorigenesis and anoikis resistance of nonsmall-cell lung cancer (NSCLC) by FAK/Src signaling, verified in NSCLC patients [50]. Platelet-derived growth factor receptor (PDGFR) increased the phosphorylation of Src Tyr419 and induced metastasis in lung cells [48].…”