Long non-coding RNA HOTAIR and HOTTIP as potential biomarkers for hepatitis C virus genotype 4-induced hepatocellular carcinoma

Abstract

Background: Long non-coding RNAs (lncRNAs) homeobox (Hox) transcript antisense intergenic RNA (HOTAIR) and HOXA transcript at the distal tip (HOTTIP) have been suggested to be implicated in liver cancer tumorigenesis and progression; however, little is known about the role of the plasma HOTAIR and HOTTIP in liver cancer diagnosis and prognosis. The current study aimed at measuring the plasma levels of long non-coding RNAs (HOTAIR and HOTTIP) expression in chronic liver disease (CLD) due to HCV genotype 4 infection with/without cirrhosis and HCC patients in an attempt to evaluate the potential benefits of these new circulating as non-invasive diagnostic biomarkers and a novel therapeutic strategy for liver cirrhosis and carcinogenesis of Egyptian patients. Hundred subjects were included in this study, divided into two groups; group I (50 patients) were classified into subgroup Ia (CLD without cirrhosis, n = 25) and subgroup Ib (CLD with cirrhosis, n = 25), group II (CLD patients with HCC, n = 25), and control (healthy volunteer, n = 25). The expression of lncRNAs (HOTAIR and HOTTIP) genes was analyzed by real-time PCR. Results: LncRNAs (HOTAIR and HOTTIP) showed upregulation in all diseased groups, which was in consistent with the progression of the disease toward the HCC stage. In addition, HOTAIR and HOTTIP showed a diagnostic ability to discriminate between cases of cirrhosis and HCC compared with healthy control (p < 0.001), while HOTAIR and HOTTIP did not show a discrimination significant differences between cirrhotic cases and non-cirrhotic cases. By using receiver operating characteristic curve (ROC) analysis, it was found that LncRNAs (HOTAIR and HOTTIP) could diagnose liver cancer with 64.0% sensitivity and 86.0% specificity and 48.0% sensitivity and 88.0% specificity. Furthermore, both genes can be considered as the predictor and prognostic parameters for cirrhosis (OR = 1.111, p = 0.05) and (OR = 1.07, p = 0.05) respectively, and HCC (OR = 1.047, p = 0.01) and (OR = 1.05, p = 0.003). The increased HOTAIR and HOTTIP expression were associated with advanced tumor stages and higher grades. Conclusion: These results strongly prompt us that HOTAIR and HOTTIP genes can be used as non-invasive prognostic biomarkers and new therapeutic targets for HCV genotype 4-induced HCC.

lnc‐HOTAIR predicts hepatocellular carcinoma in chronic hepatitis C genotype 4 following direct‐acting antivirals therapy

“…They found a significant upregulation of lnc-HOTAIR gene in patients with cirrhosis and HCC, when compared to controls (p < .001). 34 Moreover, there was a significant upregulation in lnc-HOTAIR gene expression among patients with HCC, when compared to those with chronic HCV regardless the cirrhosis status. 34 F I G U R E 3 A Kaplan-Meier curve demonstrating a significant association between the higher expression level of lnc-HOTAIR more than 68 (A), ATG-7 more than 114 (B), and shorter OS in DAAs related HCC patients.…”

“…34 Moreover, there was a significant upregulation in lnc-HOTAIR gene expression among patients with HCC, when compared to those with chronic HCV regardless the cirrhosis status. 34 F I G U R E 3 A Kaplan-Meier curve demonstrating a significant association between the higher expression level of lnc-HOTAIR more than 68 (A), ATG-7 more than 114 (B), and shorter OS in DAAs related HCC patients. In addition, expression of lnc-HOTAIR more than 68 was significantly associated with shorter DFS (C) (p = .04), however, no significant association was reached between DFS and ATG-7 expression (D) (p > .05).…”

“…26 Moreover, it was demonstrated that the expression level of lnc-HOTAIR is markedly higher in HCC hepatic tissue compared to noncancerous tissue. [30][31][32][33] In a recent study of Roshdy et al, 34 100 patients were studied to investigate plasma levels of lnc-HOTAIR and lnc-HOXA transcript at the distal tip (HOTTIP) as early biomarkers for HCV genotype 4 induced HCC. They found a significant upregulation of lnc-HOTAIR gene in patients with cirrhosis and HCC, when compared to controls (p < .001).…”

“…In terms of lnc-HOTAIR and ATG-7, patients with HCC had significantly higher median expression levels of HOTAIR (Figure 2A) of (68 vs. 24; p = .001) and ATG-7 ( Figure 2B) of (114 vs. 51; p = .001, respectively. Meanwhile, high HCV-RNA viral load ( Figure 2C), BCLC-B ( Figure 2D), increased alpha-fetoprotein (AFP) level (>200 IU/ml), the presence of lymph nodal infiltration, extrahepatic metastasis ( Figure 2E), and large tumor size (>5 cm) were significantly correlated with higher expression levels of lnc-HOTAIR of (94 vs. 52; p = .001), (79 vs. 43; p = .04), (92 vs. 52; p = .006), (80 vs. 34; p = .001), (91 vs. 34; p = .001), and (92 vs. 52; p = .01), respectively. On the other hand, no significant association was observed between the expression of lnc-HOTAIR and ATG-7 and the onset HCC in HCV patients following DAAs (p > .05; Table 1).…”

LncRNAs in HCV Infection and HCV-Related Liver Disease

“…AF070632 did not validate in patients, but this could be attributed to its specific disease stage downregulation, which was not accounted for in the tumor biopsies. 5 Promotes tumorigenesis by suppression of miR-122 and activation of Cyclin G1 [136,137] HOTTIP up 5 Unknown in HCC; promotes cell proliferation and invasion by modulating HOXA13 in pancreatic cancer [136,138] Zheng et al [123] used TCGA data to identify deregulated lncRNAs in HCC samples from patients infected with HBV, HCV, or both. Remarkably, in all cases, a collection of 10 lncRNAs was significantly deregulated.…”