The inhibition of Wnt restrain KRASG12V-driven metastasis in non-small-cell lung cancer
Journal
Cancers
Journal Volume
12
Journal Issue
4
Date Issued
2020
Author(s)
Abstract
The KRAS mutations have been an obstacle to identify therapeutic targets in cancer treatment. In this work, we clarified the distinct metastasis pattern of non-small-cell lung carcinoma (NSCLC) induced by KRASG12V/KRASG12D mutations and inhibited the KRASG12V mediated metastasis by Wnt inhibitor. First, we found that KRASG12V induced more aggressive phenotype in vitro and in vivo experiments. The Gene Set Enrichment Analysis (GSEA) results of H838 KRASG12V cells showed a significant negative correlation with RhoA-related signaling. Following this clue, we observed KRASG12D induced higher activation of RhoA and suppressed activation of Wnt/β-catenin in H838KRASG12D cells. The restored activation of Wnt/β-catenin in H838KRASG12D cells could be detected when expression with a dominant-negative mutant of RhoA or treatment with RhoA inhibitor. Furthermore, the Wnt inhibitor abolished the KRASG12V-induced migration. We elucidated the importance of the axis of RhoA/Wnt in regulatory NSCLC metastasis driven by KRAS mutations. Our data indicate that KRASG12V driven NSCLC metastasis is Wnt-dependent and the mechanisms of NSCLC metastasis induced by KRASG12V/KRASG12D is distinct. ? 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Subjects
KRASG12D; KRASG12V; Metastasis; NSCLC; RhoA; Wnt/β-catenin
SDGs
Other Subjects
beta catenin; K ras protein; lgk 974; nerve cell adhesion molecule; protein inhibitor; RhoA guanine nucleotide binding protein; unclassified drug; uvomorulin; vimentin; Wnt protein; animal experiment; animal model; animal tissue; Article; cell invasion; cell migration; cell proliferation; cell structure; controlled study; down regulation; epithelial mesenchymal transition; gene expression profiling; gene mutation; human; human cell; in vitro study; in vivo study; MAPK signaling; metastasis; mouse; NCI-H838 cell line; non small cell lung cancer; nonhuman; nude mouse; oncogene K ras; phenotype; protein expression; SK-LU-1 cell line; Wnt signaling
Publisher
MDPI AG
Type
journal article