Long non‑coding RNA DUXAP8 promotes tumorigenesis by regulating IGF1R via miR‑9‑3p in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide with a low 5-year survival rate. Long non-coding RNA (lncRNA) double homeobox A pseudogene 8 (DUXAP8) is an oncogene and a potential biomarker in various tumors, such as ovarian, colorectal and non-small-cell lung cancer. However, the function and molecular mechanism underlying DUXAP8 in HCC progression is not completely understood. The expression of DUXAP8, microRNA (miR)-9-3p and insulin-like growth factor 1 receptor (IGF1R) in HCC tissues and cells was detected via reverse transcription-quantitative PCR. The expression levels of IGF1R and epithelial-mesenchymal transition-associated proteins (Snail, Slug, E-cadherin, N-cadherin and vimentin) were assessed via western blotting. The effects of DUXAP8, miR-9-3p and IGF1R on proliferation, migration and invasion were examined by conducting Cell Counting Kit-8 and Transwell assays, respectively. The interaction between miR-9-3p and DUXAP8 or IGF1R was predicted using StarBase or TargetScan, and further assessed using dual luciferase reporter and RNA immunoprecipitation assays. DUXAP8 and IGF1R were upregulated and miR-9-3p was downregulated in HCC tissues and cells compared with adjacent healthy tissues and a normal liver cell line, respectively. miR-9-3p overexpression decreased the protein expression level of IGF1R, and miR-9-3p knockdown enhanced the protein expression level of IGF1R in HCC cells compared with the corresponding control groups. Moreover, compared with the corresponding control groups, DUXAP8 knockdown and miR-9-3p overexpression increased E-cadherin protein expression levels, and decreased Snail, Slug, N-cadherin and vimentin protein expression levels. However, miR-9-3p inhibitor and IGF1R overexpression reversed DUXAP8 knockdown-and miR-9-3p overexpression-induced effects, respectively. In addition, compared with the corresponding control groups, DUXAP8 knockdown and miR-9-3p overexpression suppressed proliferation, migration and invasion, which was reversed by miR-9-3p inhibitor and IGF1R overexpression, respectively. Moreover, miR-9-3p as the target of DUXAP8 and IGF1R as the target of miR-9-3p were verified in HCC cells. lncRNA DUXAP8 contributed to HCC tumorigenesis via the miR-9-3p/IGF1R axis, providing a novel therapeutic approach for HCC diagnosis and treatment.

Promising Biomarkers in Head and Neck Cancer: The Most Clinically Important miRNAs

“…MiR-9 (miR-9-5p and miR-9-3p) is a miRNA that is very often deregulated in cancer; however, its biological role has proven to be quite complex, as it can behave as an oncomiR in certain cases, and as an onco-suppressor miRNA in other cases [ 181 , 182 ]. MiR-9 appears to be downregulated in gastric [ 183 ], colorectal [ 184 ], and hepatocellular carcinoma [ 185 ], and advanced non-small cell lung cancer [ 186 ], but upregulated in breast [ 187 ] and cervical cancer [ 188 ]. In HNC, the regulation and functional role of miR-9 seem to vary, and might depend on the anatomic site or cellular context.…”

LncRNA DUXAP8 as a prognostic biomarker for various cancers: A meta-analysis and bioinformatics analysis

“…We excluded duplicate studies, studies irrelevant to the research subject, and studies that did not provide sufficient data. Therefore, there are a total of 25 studies that meet the final analysis conditions ( Ma et al, 2017b ; Xu et al, 2017 ; Lian et al, 2018 ; Lin et al, 2018 ; Du et al, 2019 ; Jiang et al, 2019 ; Chen et al, 2020a ; Chen et al, 2020b ; He et al, 2020 ; Hu et al, 2020 ; Nie et al, 2020 ; Wang et al, 2020 ; Wei et al, 2020 ; Yin et al, 2020 ; Zhang et al, 2020 ; Zhao et al, 2020 ; Chen et al, 2021a ; Li et al, 2021a ; Arabpour et al, 2021 ; Yang et al, 2021a ; Chen et al, 2021b ; Guan et al, 2021 ; Pang and Yang, 2021 ; Xing et al, 2021 ; Zhai et al, 2021 ). Moreover, the main features of the included studies have been summarized in Supplementary Table S1 .…”

“…All the included studies from 2016 to 2021 have been implemented and published in China except one study carried out in America. In total, 17 cancer types were included in our study: gastric cancer (GC) ( Ma et al, 2017b ), non-small cell lung cancer (NSCLC) ( Yin et al, 2020 ; Chen et al, 2021a ), cervical cancer (CC) ( Chen et al, 2020b ), oral cancer (OC) ( Chen et al, 2020a ), colorectal cancer (CRC) ( Du et al, 2019 ; He et al, 2020 ), papillary thyroid carcinoma (PTC) ( Pang and Yang, 2021 ), LGG ( Zhao et al, 2020 ), PAAD ( Lian et al, 2018 ), hepatocellular carcinoma (HCC) ( Jiang et al, 2019 ; Hu et al, 2020 ; Wang et al, 2020 ; Wei et al, 2020 ; Zhang et al, 2020 ; Guan et al, 2021 ), acute myeloid Leukemia (AML) ( Zhai et al, 2021 ), BLCA ( Lin et al, 2018 ), KIRC ( Xing et al, 2021 ), neuroblastoma ( Nie et al, 2020 ), ovarian cancer ( Li et al, 2021a ), osteosarcoma ( Yang et al, 2021a ), renal cell carcinoma (RCC) ( Xu et al, 2017 ), melanoma ( Chen et al, 2021b ), breast cancer (BC) ( Arabpour et al, 2021 ).…”

“…There were 25 studies ( Ma et al, 2017b ; Xu et al, 2017 ; Lian et al, 2018 ; Lin et al, 2018 ; Du et al, 2019 ; Jiang et al, 2019 ; Chen et al, 2020a ; Chen et al, 2020b ; He et al, 2020 ; Hu et al, 2020 ; Nie et al, 2020 ; Wang et al, 2020 ; Wei et al, 2020 ; Yin et al, 2020 ; Zhang et al, 2020 ; Zhao et al, 2020 ; Chen et al, 2021a ; Li et al, 2021a ; Arabpour et al, 2021 ; Yang et al, 2021a ; Chen et al, 2021b ; Guan et al, 2021 ; Pang and Yang, 2021 ; Xing et al, 2021 ; Zhai et al, 2021 ), consisting of 4,757 patients, included for OS analysis. A correlation analysis has been performed to explore between DUXAP8 and the poor OS in patients diagnosed with cancer.…”

“…DUXAP8 is significantly overexpressed in cancer tissues compared to nearby non-tumor tissues, according to observations ( Ma et al, 2017b ; Du et al, 2019 ; Chen et al, 2020a ; Chen et al, 2020b ; He et al, 2020 ; Yin et al, 2020 ; Chen et al, 2021a ). DUXAP8 exerts an essential role in tumorigenesis, proliferation, migration, invasion, and inhibition of apoptosis, which means that DUXAP8 acts as an oncogene in the occurrence and development of various malignant tumors ( Jiang et al, 2019 ; Hu et al, 2020 ; Wang et al, 2020 ; Wei et al, 2020 ; Zhang et al, 2020 ; Guan et al, 2021 ). In addition, high-quality meta-analysis has been increasingly considered one of the keys and significant tools for achieving evidence ( Yao et al, 2016 ; Tian et al, 2017 ; Li et al, 2018 ; Yang, 2018 ; Yang et al, 2018 ; Yan et al, 2019 ).…”