Identification of a Novel Eight-lncRNA Prognostic Signature for HBV-HCC and Analysis of Their Functions Based on Coexpression and ceRNA Networks

Abstract

Studies have demonstrated the prognosis potential of long noncoding RNAs (lncRNAs) for hepatocellular carcinoma (HCC), but specific lncRNAs for hepatitis B virus- (HBV-) related HCC have rarely been reported. This study was aimed at identifying a lncRNA prognostic signature for HBV-HCC and exploring their underlying functions. The sequencing dataset was collected from The Cancer Genome Atlas database as the training set, while the microarray dataset was obtained from the European Bioinformatics Institute database (E-TABM-36) as the validation set. Univariate and multivariate Cox regression analyses identified that eight lncRNAs (TSPEAR-AS1, LINC00511, LINC01136, MKLN1-AS, LINC00506, KRTAP5-AS1, ZNF252P-AS1, and THUMPD3-AS1) were significantly associated with overall survival (OS). These eight lncRNAs were used to construct a risk score model. The Kaplan-Meier survival curve results showed that this risk score can significantly differentiate the OS between the high-risk group and the low-risk group. Receiver operating characteristic curve analysis demonstrated that this risk score exhibited good prediction effectiveness (area under the curve AUC=0.990 for the training set; AUC=0.903 for the validation set). Furthermore, this lncRNA risk score was identified as an independent prognostic factor in the multivariate analysis after adjusting other clinical characteristics. The crucial coexpression (LINC00511-CABYR, THUMPD3-AS1-TRIP13, LINC01136-SFN, LINC00506-ANLN, and KRTAP5-AS1/TSPEAR-AS1/MKLN1-AS/ZNF252P-AS1-MC1R) or competing endogenous RNA (THUMPD3-AS1-hsa-miR-450a-TRIP13) interaction axes were identified to reveal the possible functions of lncRNAs. These genes were enriched into cell cycle-related biological processes or pathways. In conclusion, our study identified a novel eight-lncRNA prognosis signature for HBV-HCC patients and these lncRNAs may be potential therapeutic targets.

Identification of a Five-Autophagy-Related-lncRNA Signature as a Novel Prognostic Biomarker for Hepatocellular Carcinoma

“…The mutation of TP53, which was proven the most common mutation in patients with liver cancer, showed higher frequency in the high-risk group. Previous study has reported that TP53 inhibited autophagy by inhibiting AMPK but activating mTOR signaling pathway (Zhao et al, 2020 ). As such, it is interesting to further explore the casual role between TP53 mutation and dysregulated autophagy during HCC development.…”

“…CYTOR has been reported as an adverse factor of pan cancers via promoting proliferation, migration, invasion, metastasis, and drug resistance of tumor cells (Wang et al, 2018 ; Zhang and Li, 2018 ; Liu et al, 2019a ; Zou et al, 2019 ; Chen W. et al, 2020 ; Zhu et al, 2020a ). MKLN1-AS has also been reported to be a risk factor of liver cancer (Xiao et al, 2019 ), although it is also reported as a protective lncRNA of HCC in HBV-positive patients, which might due to the analysis being restricted to HBV-HCC (Zhao et al, 2020 ). Despite this, our signature could also effectively distinguish the different OS outcomes of high- and low-risk groups of HBV-HCC patients.…”

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“…The mutation of TP53, which was proven the most common mutation in patients with liver cancer, showed higher frequency in the high-risk group. Previous study has reported that TP53 inhibited autophagy by inhibiting AMPK but activating mTOR signaling pathway (Zhao et al, 2020). As such, it is interesting to further explore the casual role between TP53 mutation and dysregulated autophagy during HCC development.…”

“…CYTOR has been reported as an adverse factor of pan cancers via promoting proliferation, migration, invasion, metastasis, and drug resistance of tumor cells (Wang et al, 2018;Zhang and Li, 2018;Liu et al, 2019a;Zou et al, 2019;Zhu et al, 2020a). MKLN1-AS has also been reported to be a risk factor of liver cancer (Xiao et al, 2019), although it is also reported as a protective lncRNA of HCC in HBV-positive patients, which might due to the analysis being restricted to HBV-HCC (Zhao et al, 2020). Despite this, our signature could also effectively distinguish the different OS outcomes of highand low-risk groups of HBV-HCC patients.…”

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“…The relationship between lncRNAs and cancer progression has been proven from various recent research works. Moreover, the development of genome-wide sequencing technologies has accelerated the identification of prognostic markers for HCC (Lin et al, 2018;Zhang et al, 2020;Zhao et al, 2020). However, a nomogram combining the molecular biomarkers with clinical characteristics has not been determined yet.…”