Biological function of UCA1 in hepatocellular carcinoma and its clinical significance: Investigation with in vitro and meta-analysis

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Abstract

Urothelial cancer associated 1 (UCA1) was upregulated in hepatocellular carcinoma (HCC) tissues and cell lines, and the expression of UCA1 was associated with several clinical features and malignant behaviours in HCC. However, none of these findings completely interpreted the role of UCA1 in HCC. We conducted this investigation to validate the expression of UCA1 and its relationship with Tumor Node Metastasis (TNM) stage in 41 HCC tissues and their paired noncancerous adjacent tissues by real-time qPCR. Furthermore, we also explored the biological functions of UCA1 in vitro with HCC cell lines. Most importantly, we conducted a comprehensive meta-analysis and bioinformatics investigation based on peer-reviewed literature and in silico approaches to further summarise the clinical value and functions of UCA1 in HCC. UCA1 expression was remarkably upregulated in HCC tissues, and its expression was profoundly higher in advanced stages than in early stages. Reducing the expression levels of UCA1 suppressed the proliferation and induced apoptosis of HCC cells. Furthermore, the present meta-analysis validated that up-regulated UCA1 was closely related to larger tumour size and advanced TNM stages, and the overexpression of UCA1 was significantly correlated with a shorter OS. Additionally, according to GO analysis, the target genes were found concentrated in the following biological processes: extracellular matrix organisation, cilium assembly and cilium morphogenesis. KEGG pathway analysis showed that the UCA1-related genes were significantly enriched in the following pathways: hippo signalling pathway, bile secretion and gastric acid secretion. This evidence hinted that UCA1 could play an indispensable proliferation-related key role in HCC via the hippo signalling pathway. However, the exact molecular mechanism needs to be verified with future functional experiments.

Introduction

Hepatocellular carcinoma (HCC), one subtype of liver cancer originating from hepatic cells, has the highest incidence of any cancer in the world. HCC is also the second main cause of cancer-related death in males and the sixth main cause in females worldwide. HCC mainly occurs in Southeast Asia and East Asia, especially in China, as well as in northern and western Africa [1,2]. The pathogenesis of HCC involves several factors, including hepatitis B virus (HBV) chronic infection, hepatitis C virus (HCV) infection, unrestrained consumption of alcohol, non-alcoholic fatty liver disease, diabetes and dietary exposure to aflatoxin [[3], [4], [5]]. Presently, even though the 5-year survival rate of HCC patients has been improved via resection in the early stage and liver transplantation, metastasis and recurrence remain the main reason for treatment failure [[6], [7], [8], [9]]. Furthermore, when patients are diagnosed with HCC, most are at intermediate or advanced stages; this is yet another reason for poor prognosis of HCC [[10], [11], [12]]. Hence, determining the molecular mechanisms underlying the early pathogenesis of HCC is urgently needed.

Urothelial cancer associated 1 (UCA1, Gene ID: 652995), also known as CUDR (cancer upregulated drug resistant) noncoding RNA, is a long noncoding RNA (lncRNA) that has been reported to be universally upregulated in many malignancies [[13], [14], [15], [16], [17]]. Moreover, UCA1 can act as an unfavourable biomarker for predicting malignant phenotypes and prognosis [[18], [19], [20]]. In breast cancer, UCA1 could boost the tamoxifen resistance of tumour cells [21]. This suggests that UCA1 may also play a specific role in the treatment of different malignancies.

There is some evidence to suggest that UCA1 is notably upregulated in HCC serum and may be applied as a non-invasive marker for HCC screening and prognostic prediction [[22], [23], [24]]. Additionally, UCA1 has been upregulated in HCC tissues and cell lines, and the expression of UCA1 is associated with several clinical features and malignant behaviours in HCC [[23], [24], [25], [26], [27], [28], [29]]. However, none of these findings have completely interpreted the role of UCA1 in HCC, and the sample size used in each study was small. Thus, we conducted this investigation to validate the expression of UCA1 and its relationship with TNM stage in 41 HCC tissues and their paired noncancerous adjacent tissues by real-time qPCR. Furthermore, we also explored the biological functions of UCA1 in vitro with HCC cell lines. Most importantly, we conducted a comprehensive meta-analysis and bioinformatics investigation based on peer-reviewed literature and in silico approaches to further summarise the clinical value and functions of UCA1 in HCC.

Section snippets

Quantitative real-time RT-PCR assay

In total, 41 HCC cases were gathered from First Affiliated Hospital of Guangxi Medical University (Nanning, Guangxi, China) from December 2016 to December 2017. The tissues were collected randomly from patients who were undergoing surgical resection without treatment. The informed consent to use the samples in research was provided by the patients or their families. Formal ethical approvement was given by the Ethics Committee of The First Affiliated Hospital of Guangxi Medical University to

UCA1 expression was remarkably upregulated in HCC tissues by in-house qRT-PCR

The transcription level of UCA1 was more significantly upregulated in HCC tissues than in adjacent noncancerous tissues (P = 0.0006, Fig. 1A) based on qRT-PCR. We also observed that the expression of UCA1 was associated with TNM stage. UCA1 expression was profoundly higher in advanced stages of III and IV than in early stages of I and II (Fig. 1B). Furthermore, the AUC of UCA1 was 0.734 (95% CI, 0.626–0.841, P = 0.0003, Fig. 1C).

Function of UCA1 siRNA on malignant phenotypes of HCC cells

The siRNA transfection efficiency was more than 90%, and UCA1

Discussion

The stubbornly high morbidity and mortality of HCC warrants a deeper understanding of the biological process underlying this situation. Several recent studies have reported that lncRNA is becoming increasingly popular for monitoring the clinical outcomes and targeted therapy of HCC patients due to its diverse functions [[43], [44], [45]]. Here, our findings illuminated the significantly upregulated lncRNA UCA1 in HCC tissues. Reducing the expression levels of UCA1 suppressed the proliferation

Conclusion

Taken together, our results underscore that the lncRNA UCA1 siRNAs were notable in inhibiting proliferation and inducing apoptosis of HCC cells. Significant clinical values consistent with its functional phenotype indicate the significant potential of UCA1 in the screening, prognosis and treatment evaluation of HCC.

Disclosure of conflict of interest

The authors declare no competing financial interests.

Acknowledgment

The study was supported by Innovation Project of Guangxi Graduate Education (YCBZ2017040).

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