LINK-A Long Non-Coding RNA (lncRNA) Participates in Metastasis of Ovarian Carcinoma and Upregulates Hypoxia-Inducible Factor 1 (HIF1α)

Abstract

Background The functionality of LINK-A lncRNA as an oncogenic lncRNA has only been characterized in triple-negative breast cancer. The present study investigated the possible involvement of LINK-A in ovarian carcinoma. Material/Methods We enrolled 76 patients with ovarian carcinoma. Quantitative real-time PCR (qRT-PCR) was performed to analyze LINK-A expression in ovarian biopsies. Effects of LINK-A overexpression on HIF1α and cancer cell migration and invasion were assessed. Results We found that LINK-A was significantly higher in ovarian carcinoma patients than in healthy controls in ovarian biopsies and in serum. LINK-A expression effectively distinguished patients with metastatic ovarian carcinoma from healthy controls. LINK-A overexpression promoted cancer cell migration and invasion, and also upregulated the expression of HIF1α. Conclusions LINK-A lncRNA may be involved in the metastasis of ovarian carcinoma by upregulating HIF1α.

The role of long intergenic non-coding RNA for kinase activation (LINK-A) as an oncogene in non-small cell lung carcinoma

“…According to Wu et al, LINK-A is up-regulated in human glioma cells and LDH-A is regulated by LINK-A , which mediates the proliferation and invasion of glioma cells 16 . In addition, Zhang et al have recently reported that LINK-A is higher in ovarian carcinoma patients compared with healthy controls, which leads to the metastasis of ovarian carcinoma by up-regulation of HIF1α 15 . In another study conducted by our group, we observed elevated expression of LINK-A in Iranian epithelial ovarian cancer patients, which also was correlated with higher stages and grades of cancer 45 .…”

“…Considering its crucial role in cancer progression, HIF1α as a transcription factor is involved in several signaling pathways and overlapping molecular mechanisms, each of which could be an encouraging target to be investigated in cancer studies 13 , 14 . In addition to its roles in breast cancer, LINK-A has oncogenic role in ovarian cancer 15 , glioma 16 , and lung cancer 17 , 18 . LINK-A acts as a cytoplasmic scaffold in triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) leads to the normoxic stabilization of HIF1α 12 .…”

Long-Noncoding RNA (lncRNA) in the Regulation of Hypoxia-Inducible Factor (HIF) in Cancer

“…Corroborating the findings of Lin et al [46], a relationship of LINK-A and HIF-1α could also be observed in ovarian carcinoma as well as in osteosarcoma. In cell lines of both cancer types overexpression of LINK-A resulted in likewise increased HIF-1α levels and proliferation, migration and invasion [44,45]. The connection between LINK-A and HIF-1α was also reported in non-malignant diseases such as diabetic nephropathy, further supporting the existing body of evidence [101].…”

“…PVT1 ↑ increases HIF-1α expression and stability [41][42][43] LINK-A ↑ increases HIF-1α stability and activation [44][45][46] lincRNA-p21 ↑ increases HIF-1α protein stability [40] HISLA ↑ increases HIF-1α protein stability [47] GHET1 ↑ increases HIF-1α expression and stability [39,48] MIR31HG/HIFCAR ↑ enhances HIF-1α activation [38,49] DANCR ↑ stabilizes HIF-1α mRNA [50] CASC9 ↑ increases HIF-1α protein stability [51,52] MALAT1 ↑ increases HIF-1α protein stability [53] MTA2TR ↑ increases HIF-1α protein stability [54] UBE2CP3 ↑ no specific mechanism defined [55] AWPPH ↑ no specific mechanism defined [56] LET ↓ decreases HIF-1α mRNA stability [57] ENST00000480739 ↓ decreases HIF-1α protein stability [58] CPS1-IT1 ↓ decreases HIF-1α activation [59][60][61] HITT ↓ inhibits HIF-1α transcription and translation [35,36] MEG3 ↓ Increases HIF-1α expression [62] IDH1-AS1 ↓ decreases HIF-1α protein stability [37] PIN1-v2 ↓ inhibits HIF-1α transcription [63] HOTAIRM1 ↓ post-transcriptionally inhibits HIF-1α expression [64]…”

Circulating non-coding RNAs in recurrent and metastatic ovarian cancer

“…LINK-A overexpression promoted cell migration and invasion by up-regulating TGF-β1 and activating the TGF-β pathway in OC cells [158] . Finally, Zhang et al [159] also found that the serum levels of LINK-A were higher in OC patients than in healthy controls and associated with metastasis. LINK-A overexpression promoted migration and invasion, and upregulated the expression of HIF1a in OC cells [159] .…”