miR-122-5p Expression and Secretion in Melanoma Cells Is Amplified by the LPAR3 SH3–Binding Domain to Regulate Wnt1

Abstract

The lysophosphatidic acid receptor-3 (LPAR3) is a G protein-coupled receptor that mediates viability among malignant cells and aggressiveness among certain tumors. The study's objective was to determine the interplay between LPAR3 and miRNAs to impact key cellular signaling pathways. Using SK-Mel-2 and SK-Mel-5 melanoma cells, wild-type and mutated receptors were stably expressed to explore molecular mechanisms. LPAR3 signaling induced miR-122-5p intracellularly and subsequently its inclusion into exosomes. This amplification resulted in less abundant Wnt1, maintenance of GSK3 inactivation and to a lesser extent, partial degradation of b-catenin. The surge in miR-122-5p and reduction in Wnt1 originated from signaling at the Src homology 3 (SH3) ligand-binding motif within the third intracellular loop of LPAR3, because mutant receptors did not increase miR-122-5p and had a weakened capacity to reduce Wnt1. In addition, a key mediator of melanoma survival signaling, the peroxisome proliferator-activated receptor gamma coactivator 1-a (PPARGC1A/PGC1), was involved in miR-122-5p transcription. In conclusion, this study highlights the powerful role miRNAs have in fine-tuning specific G protein-coupled receptor-mediated signaling events by altering the transcription of signaling transduction pathway components. This study also identifies that LPAR3 increases miR-122-5p expression, which occurs mechanistically through the SH3 domain and helps explain why miR-122-5p increases are detected in cancer patient serum.Implications: LPAR3 is partially responsible for the production and secretion of miR-122-5p, found in the serum of a wide variety of patients with cancer.

MicroRNA Regulation of the Autotaxin-Lysophosphatidic Acid Signaling Axis

“…Among tumor cells in malignant tissue, there is a global decrease of miRNA expression inside the tumor cells when compared to normal cells in adjacent tissue, implying roles for some miRNAs as tumor suppressors [50]. We and others have observed the export of miRNAs from cancer cells during tumorigenesis, which frequently facilitates signaling events beneficial to malignancy [40,51]. This section contains examples where this occurs, but signaling outcomes are dependent upon the functional consequences of individual miRNAs.…”

“…Under this scenario, as miR-122 binds to viral RNA, there is less miR-122 available overall, which negatively impacts normal liver function and increases the risk for hepatocellular carcinoma [70]. In a normal context, miR-122 was initially thought to be a liver-specific miRNA; however, hepatocytes are not necessarily the only cell type whereby it has a role, and many other cancer subtypes show its presence [51,70,71].…”

“…Signaling through the LPAR3 caused a surge in miR-122 production within melanoma cells and also exported as cargo into exosomes [51]. Delving into this mechanism, Byrnes et al uncovered specifically that the Src homology 3 ligand-binding motif within the third intracellular loop of the receptor was responsible for the upregulation of miR-122.…”

Indoleamine 2, 3 Dioxygenase 1 Impairs Chondrogenic Differentiation of Mesenchymal Stem Cells in the Joint of Osteoarthritis Mice Model

“…Hence, the downregulation of miR-122-5p under the effect of IDO1 is the key link between IDO1 and the activation of Wnt1/β-catenin signaling pathway in the stimulated MSCs. Moreover, though the relation between Wnt1 and miR-122-5p was reported in the melanoma ( 33 ), the connection between IDO1 and miR-122-5p/Wnt1 in chondrogenic stimulated MSCs is reported for the first time in this study. Therefore, this study explores a new function of IDO1 in the synovial fluid of OA patients by which IDO1 impairs the differentiation of MSCs to mature chondrocytes; hence, IDO1 could be a promised target in the treatment of OA.…”

ZEB1-AS1/miR-133a-3p/LPAR3/EGFR axis promotes the progression of thyroid cancer by regulating PI3K/AKT/mTOR pathway

“…Lysophosphatidic acid receptor 3 (LPAR3) is the receptor of LPA and has been reported as a regulator in some diseases, such as melanoma [15]. LPAR3 has also been confirmed to be involved in PI3K/AKT pathway in ovarian cancer [16].…”