lncRNA TINCR attenuates the proliferation and invasion, and enhances the apoptosis of cutaneous malignant melanoma cells by regulating the miR‑424‑5p/LATS1 axis

Abstract

Cutaneous malignant melanoma (CMM) is responsible for ≥1/2 of skin cancer-related mortalities. The aberrant expression of long non-coding RNAs (lncRNAs) has been associated with the development of CMM. However, to the best of our knowledge, the role of the lncRNA TINCR ubiquitin domain containing (TINCR) in CMM has not been previously investigated, and thus, the current study aimed to evaluate this in vitro and in vivo . Reverse transcription-quantitative PCR (RT-qPCR) was used to analyze microRNA (miR)-424-5p expression, and RT-qPCR and western blotting were used to measure TINCR, large tumor suppressor kinase 1 (LATS1), cellular communication network factor 2 (CTGF), cellular communication network factor 1 (CCN1) and AXL receptor tyrosine kinase (AXL) mRNA and protein expression levels, respectively. Cell Counting Kit-8, flow cytometry and Transwell assays were used to detect the proliferation, apoptosis and invasion of CMM cell lines, respectively. The binding sites between TINCR and miR-424-5p were predicted using the miRDB database. A dual luciferase reporter assay and RT-qPCR were used to identify the relationship between TINCR and miR-424-5p in CMM cell lines. The bioinformatics analysis revealed that TINCR was one of the most significantly downregulated lncRNAs in CMM, and advanced stage CMM tissues showed the greatest decrease in TINCR expression. Moreover, in the collected CMM tissues and tested cell lines of the current study, TINCR expression was found to be downregulated compared with the respective controls. Notably, TINCR overexpression inhibited the expression levels of CTGF, CCN1 and AXL, decreased the proliferation and invasion, and induced the apoptosis of CMM cell lines. In addition, a mutual binding association was identified between miR-424-5p and TINCR in CMM cells. LATS1, a target of miR-424-5p, was found to be positively regulated by TINCR. TINCR activated Hippo signaling and repressed the activity of Yes 1 associated transcriptional regulator by regulating LATS1 expression, while LATS1 knockdown reversed the effect of TINCR overexpression on CMM cells. Collectively, the findings of the present study suggested that TINCR may attenuate the progression of CMM by regulating the miR-424-5p/LATS1 signaling axis. These results indicated that TINCR may play a tumor suppressive role in CMM.

Proteasomal downregulation of the pro-apoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma

“…By contrast, RASSF1A, an upstream activator of MST2, and LATS1, a downstream substrate of MST2, may work as tumour suppressors. RASSF1A expression is commonly lost in melanoma patients (Reifenberger et al, 2004), and the expression of LATS1 is often downregulated (Han et al, 2021, Yuan et al, 2015). These observations are consistent with a tumour suppressive function of MST2 signalling that is independent of YAP1.…”

“…RASSF1A is commonly lost in melanoma patients due to DNA methylation (Reifenberger et al, 2004). LATS1 levels seem to be decreased through different mechanism that include post-translational modification and long non-coding RNAs (Han et al, 2021, Yuan et al, 2015). These results suggest that loss of a functional MST2 pathway might be associated with melanoma development.…”

Fulvestrant, an estrogen receptor inhibitor, relieves postoperative hemorrhoid edema via up-regulation of miR- 424-5p

“…The fact that Fulvestrant treatment reduced ERα and VEGF expressions in primary vascular endothelial cells might suggest that Fulvestrant ameliorated inflammation. The miRNA regulatory member i.e., miR-424 is a widely studied factor, and it regulates the proliferation or growth of human cancer cells, including liver cancer, melanoma, and colorectal cancer, through the target genes [21]. It blocked E2-mediated cell multiplication in endometrial carcinoma by targeting G protein-coupled ER.…”

Regulation of LncRNAs in Melanoma and Their Functional Roles in the Metastatic Process

“…Recent transcriptomic studies revealed that lncRNAs might be engaged in regulating phenotype switches in melanoma. One is the lncRNA TINCR, whose ectopic expression reduces melanoma cell invasion and expression of invasive markers, driving the transition of invasive cells to intermediate and proliferative cell states [44,140]. TINCR is highly expressed in primary melanomas, is downregulated in metastatic melanomas, and is required to maintain the proliferative cell state.…”

“…TINCR is highly expressed in primary melanomas, is downregulated in metastatic melanomas, and is required to maintain the proliferative cell state. TINCR downregulation inhibits melanoma development in vivo by suppressing the ATF4-CHOP pathway [44] and activating the Hippo pathway [140]. However, the association of TINCR expression with melanoma clinic-pathological features and prognosis is still missing.…”