LINC00886 Facilitates Hepatocellular Carcinoma Tumorigenesis by Sequestering microRNA-409-3p and microRNA-214-5p

Abstract

Purpose As the major subtype of liver cancer, hepatocellular carcinoma (HCC) suffers from high mortality and is prone to recurrence. Long non-coding RNAs (lncRNAs) are well characterized to be pivotal players contributing to HCC pathogenesis and progression. Therefore, this study intended to probe the biological functions of LINC00886 in hepatocarcinogenesis. Patients and Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to analysis of LINC00886, microRNA-409-3p (miR-409-3p), microRNA-214-5p (miR-214-5p), RAB10 and E2F2 expression. Subcellular localization of LINC00886 was identified through a fluorescent in situ hybridization (FISH) kit and a subcellular assay. Additionally, proliferated cells were determined with EdU as well as cell counting kit-8 (CCK-8) assays. Scratch and Transwell assays were applied to detect migratory and invasive cells. Apoptotic cells were measured via TUNEL staining assay. Furthermore, targeted binding between LINC00886 and miR-409-3p or miR-214-5p was validated utilizing dual-luciferase reporter assays. RAB10, E2F2 and NF-κB signaling-associated protein levels were evaluated utilizing Western blot. Results LINC00886, RAB10 and E2F2 levels were aberrantly increased, with the abnormal expressed decline of miR-409-3p and miR-214-5p, in HCC tissues, cells and peripheral blood mononuclear cells (PBMCs). Silencing LINC00886 attenuated the proliferative, migratory, invasive, and anti-apoptotic potential of HCC cells, while LINC00886 overexpression proceeded in the contrary direction. Mechanistically, miR-409-3p and miR-214-5p were validated as binding targets for LINC00886 and inverted the biological functions of LINC00886 during HCC progression. Furthermore, the LINC00886-miR-409-3p/miR-214-5p axis could regulate RAB10 and E2F2 expression via mediating NF-κB pathway activation in hepatocarcinogenesis. Conclusion Our findings indicated that LINC00886 facilitated HCC progression via absorbing miR-409-3p or miR-214-5p to upregulate RAB10 and E2F2 through activation of NF-κB pathway, offering a promising novel target for HCC therapy.

Investigating the molecular mechanisms of microRNA‑409‑3p in tumor progression: Towards targeted therapeutics (Review)

“…MiR-409-3p not only exists in tissues and cells but also stably exists in circulating body fluids. For the most part, miR-409-3p acts as a tumor suppressor and was reported to be downregulated in a minimum of 13 cancers, including NSCLC ( 12 , 14 - 17 , 19 - 21 ), BC ( 24 , 26 , 27 , 29 , 30 ), CC ( 31 - 35 ), osteosarcoma ( 36 - 39 ), GC ( 40 - 44 ), CRC ( 45 , 46 , 48 - 51 ), OC ( 53 - 55 ), ccRCC ( 57 , 58 ), BCa ( 59 , 61 ), PTC ( 62 ), AML ( 65 , 66 ), oligodendrogliomas ( 67 ), melanoma ( 68 ), TSCC ( 70 ), glioma ( 79 ), fibrosarcoma ( 81 ) and HCC ( 83 , 84 ). However, miR-409-3p also serves as an oncogene to promote tumor progression.…”

“…In general, miR-409-3p has been strongly connected with cell growth and apoptosis in various cancers. In HCC, Li et al ( 84 ) found that silencing LINC00886 upregulated the expression of miR-409-3p, weakened the proliferation of HCC cells (Hep3B, Huh7) and promoted apoptosis. Conversely, it promoted the proliferation of Hep3B as well as Huh7 proliferation and inhibited apoptosis.…”

“…After silencing LINC00886, the expression level of miR-409-3p was upregulated, which weakened the invasion and migration of HCC cells (Hep3B, Huh7). Conversely, overexpression of LINC00886 has the opposite effect ( 84 ).…”

“…2 ). Furthermore, increasing data point to the broad expression of miR-409-3p in malignancies, particularly non-small cell lung cancer (NSCLC) ( 12 - 21 ), breast cancer (BC) ( 22 - 30 ), cervical cancer (CC) ( 31 - 35 ), osteosarcoma ( 36 - 39 ), gastric cancer (GC) ( 40 - 44 ), colorectal cancer (CRC) ( 45 - 52 ), ovarian cancer (OC) ( 53 - 56 ), renal cell carcinoma (ccRCC) ( 57 , 58 ), bladder cancer (BCa) ( 59 - 61 ), papillary thyroid cancer (PTC) ( 62 ), pancreatic cancer (PC) and biliary tract cancer (BTC) ( 63 ), diffuse large B-cell lymphoma (DLBCL) ( 64 ), acute myeloid leukemia (AML) ( 65 , 66 ), oligodendroglioma ( 67 ), melanoma ( 68 ), nasopharyngeal carcinoma (NPC) ( 69 ), tongue squamous cell carcinoma (TSCC) ( 70 ), prostate cancer (PCa) ( 71 - 76 ), meningioma ( 77 ), intracranial artery tumors ( 78 ), glioma ( 79 , 80 ), fibrosarcoma ( 81 ), glioblastoma ( 82 ) and hepatocellular carcinoma (HCC) ( 83 , 84 ). Specifically, it has been shown that miR-409-3p exerts anti- or pro-tumorigenic roles in cancer progression by targeting downstream mRNAs or modulated by the upstream regulators of long non-coding RNAs (lncRNAs) or circular RNAs (circRNAs).…”