Abstract
Abstract Precedent has established the role of the Wnt/β-catenin pathway in oncogenesis. Several members of the Wnt family are known to be tumor promoting in non-small cell lung cancer, NSCLC. In this pathway β-catenin, a downstream component, accumulates and serves as a T-cell transcription/lymphoid enhancer factor. We previously identified the Wnt ligand in the lung, Wnt 7a, as a member of the non-canonical pathway/β-catenin independent pathway, which inhibits transformed cell growth. K-homology splicing regulatory protein (KSRP) is a member of the family of AU rich element binding proteins. It possesses four K-homology motifs and causes decay of specific mRNA transcripts and regulation of miRNA. Wnt 7a positively regulates the expression of KSRP. As a result, KSRP upregulates the processing of miRNA 29b. The miRNA 29b family is comprised of 29a, 29b, and 29c. KSRP and miRNA 29b expression are elevated in nontransformed cells and alternatively, lower levels of expression are in NSCLC. The role of KSRP regulating miRNA 29b in the non-canonical Wnt pathway in the lung has previously been unknown. Over expression of KSRP through upregulation of miRNA 29b in NSCLC cells decreases cell proliferation in MTS assays, a measure of proliferation, as well as reducing colony formation in clonogenic assays. We reveal a novel association of p53 and miRNA 29b. We identified that KSRP increases PPARγ activation which in turn positively modulates miRNA 29b, resulting in upregulation of p53. The antitumorigenic effect is specific to Wnt 7a activation through Erk 5 dependent kinases.
Published Version
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