Hepatocellular carcinoma (HCC) is the digestive system cancer, which is clinically common and aggressive malignant. On account of the atypical symptoms of early HCC, the best surgical opportunity was lost when the patient came to the hospital. On the medical side, liver cancer is progressing rapidly and effectively, but it is worrying that the treatment effect and prognosis of liver cancer are still poor. Studies have shown that ncRNAs including pseudogenes, miRNAs and lncRNAs have made great contributions in the study of the occurrence and development tendency of diverse cancers[15–19]. Therefore, the molecular mechanism of liver cancer is of great significance to elucidate the pathogenesis and evolution of liver cancer, as well as to develop potential therapeutic targets. This is also the breakthrough of our research on the diagnosis and treatment of liver cancer.
In recent years, continuous research has proved that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) may be useful biomarkers in various cancer types. In the treatment of acute myeloid leukemia, LINC01018 inhibits the growth and proliferation of AML cells and promotes the apoptosis of AML cells by inhibiting Mir-499a-5p and regulating PDCD4, offering a feasible basis in theory for the treatment of AML. In addition, others have shown that SNHG11 is highly expressed in HCC, and SNHG11 promotes the growth of HCC by regulating AGO2 through miR-184, and the regulatory loop of SNHG4/ miR-184/ AGO2 is indispensable for the proliferation, migration, apoptosis and autophagy of Liver cancer cells.
This study uses Bio-informatics methods to select four data sets related to liver cancer from the GEO database, screen out the genes that are differentially expressed in liver cancer tissues, construct a lncRNA-miRNA-mRNA regulatory network of differential genes, and finally determine the existence of the LINC01018/hsa-miR-182-5p/ADH4 ceRNA regulatory network in the human body and reveals the molecular mechanism of ceRNA regulation in liver cancer. In the early stage, the important DEGS of liver cancer was screened, and the ontology enrichment analysis was carried out, and then the PPI network of DEGS was established to extract 15 central nodes which were identified as hub genes by cell type MCODE. Survival analysis of the 15 core genes showed that 10 genes are associated with a better overall survival rate, including CYP2E1, C8A, NAT2, ADH4, C7, ADH1B, RDH16, APOF, LCAT and HGFAC, and these ten genes Shows low expression in HCC tissue samples. To redetermine the prognostic value of the 10 hub genes, it was found that the expression of 3 hub genes (ADH4-RDH16-LCAT) increased, indicating a poor prognosis. Existing studies have shown that RDH16 and LCAT are both low-expressed in HCC[23–24]; among them, in terms of overall survival, patients with high ADH4 expression were significantly higher than those with low adh4 expression. Then, we used some databases to predict the upstream miRNA of the above three key genes, and finally identified a total of 24 miRNAs that may regulate the expression of core genes (7 of LCAT and 17 of ADH4, respectively). Due to the classic reverse relationship between miRNAs and target genes, the upstream miRNAs of these three genes should theoretically be tumor suppressor miRNAs for liver cancer, and are related to a good prognosis. 6 key mirnas (hsa-miR-3127-5p, hsa-miR-137-5p, hsa-miR-106a-5p, hsa-miR-23a-3p, hsa-miR-93-5p,hsa-miR-182-5p) were screened by survival analysis. Indeed, it was found that these miRNAs were negatively correlated with their related genes and were associated with a good survival rate. In our study, we concluded that hsa-miR-182-5p is closely related to liver cancer. In addition, some other studies suggest that hsa-miR-182-5p is closely related to the occurrence and pathogenesis of ovarian cancer.
Next, we used Starbase to predict 34 potential lncRNAs upstream of the above 6 mirnas, and then used GEPIA database to analyze the expression of these lncRNAs in liver cancer. It was found that 4 lncRNAs (LINC01018-LINC00261-AC144652.1-TMEM254-AS1) combined with common miRNAs were down-regulated and had good correlation, among which LINC00261 and LINC01018 had good prognosis. It can be seen from the gene expression level that the expression level of LINC01018 in liver cancer is significantly down-regulated, from which it can be concluded that LINC01018 is negatively correlated with hsa-miR-182-5p-ADH4. Some studies have investigated the possible mechanism of LINC01018 in the regulation of liver cancer progression, and it is believed that over-expression of LINC01018 may be an inhibitor of HCC. This study also supports our results.
Combining the relationship between the above-mentioned genes and upstream miRNA and lncRNA, we finally constructed a regulatory network of LINC01018/hsa-miR-182-5p/ADH4 axis. It is speculated that this axis may be involved in the survival of liver cancer. Moreover, according to the previous functional enrichment analysis, we believe that this regulatory axis may regulate the occurrence and development of liver cancer by regulating the expression levels of key proteins and phosphorylated proteins in GO and KEGG signaling pathways.
According to database exploring, it can be concluded that the expression of hsa-miR-182-5p and ADH4 in hepatocellular carcinoma is negatively correlated, and LINC01018 and hsa-miR-182-5p-ADH4 are also negatively correlated, which is in line with the outcome forecast. It shows that LINC01018, hsa-miR-182-5p, and ADH4 have a strong correlation in tumors. LINC01018 regulates ADH4 to inhibit the growth of LIHC cells by inhibiting hsa-miR-182-5p, which provides a feasible theoretical basis for the treatment of HCC.
There are still some inadequacies in the study. Constructing the lncRNA-miRNA-mRNA ceRNA regulatory network by using the public online database structure, we found the existence of LINC01018/ HSA-Mir-182-5p/ADH4 ceRNA regulatory network in human body. Besides, this network has the possibility of becoming an immune checkpoint inhibitor for liver cancer. However, the mechanism of this regulatory network in liver cancer and the interaction mechanism among LINC01018, hSA-Mir-182-5p and ADH4 need to be explored at a deeper level.