Down-Regulation of Canonical and Up-Regulation of Non-Canonical Wnt Signalling in the Carcinogenic Process of Squamous Cell Lung Carcinoma

Abstract

The majority of lung cancers (LC) belong to the non-small cell lung carcinoma (NSCLC) type. The two main NSCLC sub-types, namely adenocarcinoma (AC) and squamous cell carcinoma (SCC), respond differently to therapy. Whereas the link between cigarette smoke and lung cancer risk is well established, the relevance of non-canonical Wnt pathway up-regulation detected in SCC remains poorly understood. The present study was undertaken to investigate further the molecular events in canonical and non-canonical Wnt signalling during SCC development. A total of 20 SCC and AC samples with matched non-cancerous controls were obtained after surgery. TaqMan array analysis confirmed up-regulation of non-canonical Wnt5a and Wnt11 and identified down-regulation of canonical Wnt signalling in SCC samples. The molecular changes were tested in primary small airway epithelial cells (SAEC) and various lung cancer cell lines (e.g. A549, H157, etc). Our studies identified Wnt11 and Wnt5a as regulators of cadherin expression and potentiated relocation of β-catenin to the nucleus as an important step in decreased cellular adhesion. The presented data identifies additional details in the regulation of SCC that can aid identification of therapeutic drug targets in the future.

ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling

“…Aggregates were grown in SAGM/EGM-2/FGM-2 media at 2:2:1 ratio. After 24 h 3D aggregates were transferred on a 24 well plate (also coated with poly-HEMA) and treated with recombinant human Wnt5a at final concentration of 1 μg/ml for 72 h (Chinese Hamster Ovary Cell Line, CHO-derived Gln38-Lys380) (R&D Systems, Minneapolis, USA) [23], cisplatin (Selleck Chemicals, Houston, USA) (29.7 μM for 72 h) [25], IWR-1 (Sigma Aldrich, St. Louis, USA) (1 μM for 3 h) [23] and LiCl (Sigma Aldrich, St. Louis, USA) (10 mM for 3 h) [29]. Upon treatment they were collected in RA1 Buffer Solution for RNA isolation, into cryostat embedding medium for dissection or used for drug transporter functional test.…”

“…Previous studies have shown that Wnt pathway, although rarely mutated, is differentially regulated in LC subtypes. While beta-catenin dependent signaling can be strongly down-regulated in SCLC through over-expression of inhibitory genes differential activation of the beta-catenin dependent canonical and Ca 2+ dependent non-canonical Wnt pathways have been reported in NSCLC subtypes of AC and SCC, respectively [23,24].…”

Research on WISP1 in Lung Disease

“…Li [47] noted that WISP1 enhances alveolar capillary permeability in ALI and Konigshoff et al [63] demonstrated that anti-WISP1 antibodies attenuated bleomycin-induced lung fibrosis. Fewer reagents and progress in the lung with respect to the non-canonical pathway is apparent, although detection of hallmark regulatory proteins WNT5A or WNT11 suggests this pathway may be operative in certain forms of lung cancer [64]. Although the original observations by Slutsky et al [65,66] concluded that WNTβ-catenin signaling is important in VILI, they reported increases in indices of activation of both non-canonical (WNT5A) and canonical pathways in whole rat lung.…”

“…Fewer reagents and progress in the lung with respect to the non-canonical pathway is apparent, although detection of hallmark regulatory proteins WNT5A or WNT11 suggests this pathway may be operative in certain forms of lung cancer [64]. Although the original observations by Slutsky et al [65,66] concluded that WNTβ-catenin signaling is important in VILI, they reported increases in indices of activation of both non-canonical (WNT5A) and canonical pathways in whole rat lung. Further confirmative studies are required to identify which WNT signaling pathway is responsible for WISP1 production in the lung.…”

Differential Wnt11 Expression Related to Wnt5a in High- and Low-grade Serous Ovarian Cancer: Implications for Migration, Adhesion and Survival

“…Moreover, it has been demonstrated that activation of canonical Wnt signaling, in xenopus axis formation required the formation of Wnt11 and Wnt5a tyrosine-sulfated oligomers. Bartis et al (2013) identified Wnt11 and Wnt5a as regulators of cadherin expression and potentiated relocation of β-catenin to the nucleus as an important step in decreased cellular adhesion of squamous cell lung carcinoma. Thus, we sought to determine the role of Wnt11 in SKOV-3 cells and its possible modulation by Wnt5a in SKOV-3/Wnt5a cells.…”