Lysophosphatidic acid receptor 6 regulated by miR-27a-3p attenuates tumor proliferation in breast cancer

Abstract

Purpose Lysophosphatidic acid (LPA) is a bioactive molecule which participates in many physical and pathological processes. Although LPA receptor 6 (LPAR6), the last identified LPA receptor, has been reported to have diverse effects in multiple cancers, including breast cancer, its effects and functioning mechanisms are not fully known. Methods Multiple public databases were used to investigate the mRNA expression of LPAR6, its prognostic value, and potential mechanisms in breast cancer. Western blotting was performed to validate the differential expression of LPAR6 in breast cancer tissues and their adjacent tissues. Furthermore, in vitro experiments were used to explore the effects of LPAR6 on breast cancer. Additionally, TargetScan and miRWalk were used to identify potential upstream regulating miRNAs and validated the relationship between miR-27a-3p and LPAR6 via real-time polymerase chain reaction and an in vitro rescue assay. Results LPAR6 was significantly downregulated in breast cancer at transcriptional and translational levels. Decreased LPAR6 expression in breast cancer is significantly correlated with poor overall survival, disease-free survival, and distal metastasis-free survival, particularly for hormone receptor-positive patients, regardless of lymph node metastatic status. In vitro gain and loss-of-function assays indicated that LPAR6 attenuated breast cancer cell proliferation. The analyses of TCGA and METABRIC datasets revealed that LPAR6 may regulate the cell cycle signal pathway. Furthermore, the expression of LPAR6 could be positively regulated by miR-27a-3p. The knockdown of miR-27a-3p increased cell proliferation, and ectopic expression of LPAR6 could partly rescue this phenotype. Conclusion LPAR6 acts as a tumor suppressor in breast cancer and is positively regulated by miR-27a-3p.

Panax quinquefolium saponins attenuates microglia activation following acute cerebral ischemia‐reperfusion injury via Nrf2/miR‐103‐3p/TANK pathway

“…Subsequent studies have also shown that Nrf2 can positively regulate the transcription of miR‐103‐3p through binding to the TFBS on its promoter. It should be noted that, unlike the classical model in which miRNAs can negatively regulate the expression of target genes reported in most studies, in this study, we found that miR‐103‐3p can positively regulate the expression of TANK protein by binding to 3′UTR of TANK mRNA, which is completely consistent with the findings reported in existing studies that miRNA can positively regulate its target genes posttranscriptionally (Lei et al, 2022; Nteeba et al, 2013; Zhao et al, 2020).…”

Autotaxin and Lysophosphatidate Signaling: Prime Targets for Mitigating Therapy Resistance in Breast Cancer

“…Consistent with our findings ( Fig. 2a ) [ 15 , 40 - 42 ], LPAR6 is known to be downregulated particularly in human epidermal growth factor receptor (HER)2+ and TNBC, and decreased expression in all subtypes correlated to decreased survival [ 64 - 66 ]. LPAR6 has been proposed to function as a tumor suppressor in part through the formation of E2F family complexes capable of inducing cell cycle arrest [ 64 ].…”

“…2a ) [ 15 , 40 - 42 ], LPAR6 is known to be downregulated particularly in human epidermal growth factor receptor (HER)2+ and TNBC, and decreased expression in all subtypes correlated to decreased survival [ 64 - 66 ]. LPAR6 has been proposed to function as a tumor suppressor in part through the formation of E2F family complexes capable of inducing cell cycle arrest [ 64 ]. Mechanistically, the microRNA miR-27a-3p acts as an upstream positive regulator of LPAR6 transcription and is also suppressed in breast tumors compared to normal or benign breast tissues [ 64 ].…”

MiR-27a-3p binds to TET1 mediated DNA demethylation of ADCY6 regulates breast cancer progression via epithelial-mesenchymal transition

“…In addition, miR-27a-3p may increase the sensitivity of liver cancer to cisplatin by regulating PI3K/Akt signalling pathway ( 51 ). In breast cancer, the expression level of LPAR6 is significantly downregulated, and miR-27a-3p can positively regulate the expression of LPAR6 and affect the function of cell cycle signalling pathway ( 52 ). Previous studies have also shown that miR-27a-3p can target and negatively regulate MAGI2, which inactivates the PI3K/AKT signalling pathway by upregulating PTEN and downregulating PD-L1, thereby promoting immune evasion in breast cancer cells ( 53 ).…”