miR-218 impedes IL-6-induced prostate cancer cell proliferation and invasion via suppression of LGR4 expression

Abstract

Prostate cancer is the most common solid-organ malignancy and the second leading cause of cancer-related death in males. The oncogenic effect of leucine-rich repeat-containing G protein-coupled receptor (LGR) 4 has been recognized in the formation of various types of cancers, yet its regulatory mechanism in prostate cancer is still not fully understood. Previous study has shown that LGR4 may be a new responsive gene of interleukin-6 (IL-6) in cancer progression. In the present study, we established the LNCaP-IL-6+ cell subline by long-term incubation with a low concentration of IL-6 and explored the regulatory role of miR-218, a tumor-suppressing miRNA, in IL-6-induced LGR4 expression and LNCaP-IL-6+ cell proliferation and invasion. The results showed that miR-218 expression was gradually decreased and IL-6 expression was gradually increased in the process of prostate cancer progression from normal prostate, benign prostatic hyperplasia to prostate cancer, and from LNCaP to LNCaP-IL-6+ cells. Notably, we also found that miR-218 inhibited the expression of cell cycle regulatory protein cyclin A1 and invasion-related matrix metalloproteinase-9 protein induced by IL-6, and impeded the accelerative effect of IL-6 on LNCaP-IL-6+ cell proliferation, cell cycle progression and cell invasion. Moreover, our results confirmed that miR-218 directly targets LGR4 and modulated the PI3K/Akt and Wnt/β-catenin pathways in the LNCaP-IL-6+ cells. Taken together, these data clearly demonstrated the involvement of the miR-218/LGR4 regulatory pathway in IL-6-induced cell proliferation and invasion in LNCaP-IL-6+ cells via PI3K/Akt and Wnt/β-catenin signaling, providing new insight into therapeutics for inflammation-induced prostate cancer.

MicroRNA‑218 inhibits the migration, epithelial‑mesenchymal transition and cancer stem cell properties of prostate cancer cells

“…miR-218 can inhibit cancer cell proliferation, invasion, migration, EMT, lymph node metastasis and self-renewal in glioma, cervical cancer, gastric cancer and bladder cancer, among others (32)(33)(34)(35)(36). One study indicated that miR-218 expression is decreased in PCa, and impedes IL-6-induced PCa cell proliferation and invasion via suppression of LGR4 expression (37). miR-218 has also been demonstrated to inhibit PCa cell growth and promote apoptosis by repressing TPD52 expression (38), as well as inhibit PCa cell migration and invasion via targeting LASP1 (39).…”

The long non-coding RNA PCA3: an update of its functions and clinical applications as a biomarker in prostate cancer

“…It was also suggested that PCA3 could target miR-218-5p [18], a miRNA that negatively regulates PCa cell invasion, proliferation [19], migration [20] and tumor angiogenesis [21]. PCA3 knockdown decreased miR-218-5p expression levels in vitro and in vivo (Figure 2) and miR-218-5p suppressive effects over PCa biological functions are related to high mobility group box 1 (HMGB1) protein repression, suggesting that the PCA3 - miR-218-5p -HMGB1 axis could be important for PCa progression [18].…”

Expression of Concern: MiRNA‐218 regulates osteoclast differentiation and inflammation response in periodontitis rats through Mmp9

“…Moreover, Jia et al () found that miR‐34a could inhibit migration and invasion of tongue squamous cell carcinoma via targeting Mmp9 and Mmp14. Particularly, miR‐218, a tumour‐suppressing miRNA, has been extensively investigated in several types of cancers (Li et al, ) and is downregulated in human‐derived dental stem cells (Gay et al, ). However, the expression and function of miR‐218 and the regulatory relationship between miR‐218 and Mmp9 in periodontitis have not been fully investigated.…”