Prognostic value of long non-coding RNA MALAT1 in hepatocellular carcinoma: A study based on multi-omics analysis and RT-PCR validation

Abstract

Background: This study aimed to explore the relationship between MALAT1 and the prognosis of patients with hepatocellular carcinoma (HCC).Methods: We constructed a MALAT1 protein-protein interaction network using the STRING database and a network of competing endogenous RNAs (ceRNAs) using the StarBase database. Using data from the GEPIA2 database, we studied the association between genes in these networks and survival of patients with HCC. The potential mechanisms underlying the relationship between MALAT1 and HCC prognosis were studied using combined data from RNA sequencing, DNA methylation, and somatic mutation data from The Cancer Genome Atlas (TCGA) liver cancer cohort. Tumor tissues and 19 paired adjacent non-tumor tissues (PANTs) from HCC patients who underwent radical resection were analyzed for MALAT1 mRNA levels using real-time PCR, and associations of MALAT1 expression with clinicopathological features or prognosis of patients were analyzed using log-rank test and Gehan-Breslow-Wilcoxon test.Results: Five interacting proteins and five target genes of MALAT1 in the ceRNA network significantly correlated with poor survival of patients with HCC (p < 0.05). High MALAT1 expression was associated with mutations in two genes leading to poor prognosis and may upregulate some prognostic risk genes through methylation. MALAT1 was significantly co-expressed with various signatures of genes involved in HCC progression, including the cell cycle, DNA damage repair, mismatch repair, homologous recombination, molecular cancer m6A, exosome, ferroptosis, infiltration of lymphocyte (p < 0.05). The expression of MALAT1 was markedly upregulated in HCC tissues compared with PANTs. In Kaplan-Meier analysis, patients with high MALAT1 expression had significantly shorter progression-free survival (PFS) (p = 0.033) and overall survival (OS) (p = 0.023) than those with low MALAT1 expression. Median PFS was 19.2 months for patients with high MALAT1 expression and 52.8 months for patients with low expression, while the corresponding median OS was 40.5 and 78.3 months. In subgroup analysis of patients with vascular invasion, cirrhosis, and HBsAg positive or AFP positive, MALAT1 overexpression was significantly associated with shorter PFS and OS. Models for predicting PFS and OS constructed based on MALAT1 expression and clinicopathological features had moderate predictive power, with areas under the receiver operating characteristic curves of 0.661–0.731. Additionally, MALAT1 expression level was significantly associated with liver cirrhosis, vascular invasion, and tumor capsular infiltration (p < 0.05 for all).Conclusion:MALAT1 is overexpressed in HCC, and higher expression is associated with worse prognosis. MALAT1 mRNA level may serve as a prognostic marker for patients with HCC after hepatectomy.

Exosome Cargos as Biomarkers for Diagnosis and Prognosis of Hepatocellular Carcinoma

“…Furthermore, LINC00161 expression was positively correlated with serum AFP concentration and the TNM stage [ 81 ], indicating that exosomal lncRNAs could reflect additional clinical characteristics. Liao et al [ 82 ] analyzed the relationship between exosomal MALAT1 and the prognosis of HCC. The results show that the high expression of exosomal MALAT1 was significantly related to shorter progression-free survival and shorter overall survival, which exhibited moderate predictive power (AUC range from 0.661 to 0.731).…”

Role of ferroptosis and its non-coding RNA regulation in hepatocellular carcinoma

“…Importantly, as a key lncRNA that involved in HCC progression, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) can affect cell proliferation, apoptosis, and migration ( Lu et al, 2021 ). It has been verified that MALAT1 is overexpressed in HCC and is associated with shorter overall survival, serving as a prognostic marker for patients with HCC ( Liao et al, 2022 ). However, whether MALAT1 interacts with ferroptosis-related signaling pathways to regulate HCC biological function is needed to be further investigated.…”

Effects of DNA, RNA, and Protein Methylation on the Regulation of Ferroptosis

“…Furthermore, the role of the RNA m 6 A modification in many biological processes and diseases has been elucidated in the past decade; these processes include autophagy, cell proliferation, stem-cell renewal and differentiation, and the diseases include tumorigenesis, and cardiovascular diseases [139,146,148,149]. In the past three years, several studies have shown that RNA m 6 A marks are involved in the regulation of ferroptosis and thus affects the progression of diseases such as tumor growth and acute kidney injury [133,150,151] and that m 6 A modification regulators used in combination with ferroptosis-related genes can be diagnostic or prognostic markers for tumors in humans [130,[152][153][154][155]. Multiple m 6 A modification regulators have been shown to be aberrantly expressed in various types of tumors, and a prediction model comprising these regulators and ferroptosis-associated genes has been shown to effectively reflect the progression and prognosis of these tumor patients [23,[156][157][158][159].…”

“…Generally, hypermethylation in the promoter or transcriptional start site or hypomethylation in the coding sequence of a gene suppresses the expression of that gene. However, it should be noted that the expression of a methylated gene can be increased when either the coding sequence is hypermethylated or the promoter or transcriptional start site is hypomethylated 130 . Thus, DNA methylation in coding regions needs to be further studied, especially when no difference in overall DNA methylation is identified, and the distribution of DNA methylation throughout the genome needs to characterized.…”

“…Furthermore, the role of the RNA m 6 A modification in many biological processes and diseases has been elucidated in the past decade; these processes include autophagy, cell proliferation, stem-cell renewal and differentiation, and the diseases include tumorigenesis, and cardiovascular diseases 139 , 146 , 148 , 149 . In the past three years, several studies have shown that RNA m 6 A marks are involved in the regulation of ferroptosis and thus affects the progression of diseases such as tumor growth and acute kidney injury 133 , 150 , 151 and that m 6 A modification regulators used in combination with ferroptosis-related genes can be diagnostic or prognostic markers for tumors in humans 130 , 152 - 155 .…”