Bioinformatics and Experimental Insights Into miR-182, hsa_circ_0070269, and circ-102,166 as Therapeutic Targets for HCV-Associated HCC.
Hepatocellular carcinoma (HCC) is a type of malignant tumor and the sixth leading cause of death worldwide. It is caused by HBV, HCV infection, and alcohol consumption. MicroRNAs are typically small, non-coding RNAs that are involved in the regulation of mRNA expression. Recent studies revealed miRNAs' regulatory roles in liver cancer, linked to risk factors like HCV, HBV infection, alcoholism, drug use, and auto-immune hepatic disorders. Circular RNAs also belong to the class of non-coding RNAs; they act as ceRNAs to regulate miRNA expression and regulate different oncogenic pathways in HCC progression. This study aimed to check the hsa_circ_0070269, circ-102,166 (hsa_circ_0004913), and miR-182 expression in HCV induced HCC patients.
Data analysis was used to find out studies related to the role of hsa_circ_0070269, circ-102,166, and miR-182 in HCC; miR-182 targeted genes, their role in different diseases; and miR-182 interactions with hsa_circ_0070269 and circ-102,166 in the HCC. It was revealed that the hsa_circ_0070269, circ-102,166, and miR-182 correlations in HCV induced HCC have not been explored yet. Therefore, to validate data from literature mining, expression analysis of dysregulated hsa_circ_0070269, circ-102,166, and miR-182 was performed in HCV induced HCC patients using RT-PCR.
It was found that miR-182 was significantly upregulated and acts as an oncomiRNA in HCV induced HCC, and hsa_circ_0070269 and circ-102,166 were downregulated in HCV induced HCC. We have identified that miR-182 relative expression level was significantly high (p < 0.0029), while has_circ_0070269 (p < 0.002) and circ-102,166 (p < 0.002) were significantly downregulated in HCV-HCC patients as compared to expression in healthy individuals.
Our data revealed that miR-182 acts as an oncomiRNA in HCC development. Hsa_circ_0070269 and circ-102,166 are highly expressed in healthy controls compared to HCV induced HCC patients, can sponge miR-182 expression by acting as tumor suppressors, and can be used as biomarkers and targets for HCC treatment.
Ishaq Y
，Rauff B
，Alzahrani B
，Ikram A
，Javed H
，Abdullah I
，Mujtaba G
... -
《Cancer Reports》
Hsa_circ_0088036 promotes tumorigenesis and chemotherapy resistance in hepatocellular carcinoma via the miR-140-3p/KIF2A axis.
Hepatocellular carcinoma (HCC) is a cancer with high morbidity and mortality. There are limited treatment options, particularly for chemotherapy-resistant HCC patients. Circular RNA hsa_circ_0088036 was associated with the development of bladder cancer and non-small cell lung cancer. However, whether it might be a potential therapeutic target for HCC remains elusive.
Hsa_circ_0088036 expression was detected in HCC tumor tissues and cell lines using real-time PCR. The influences of hsa_circ_0088036 on proliferation and invasion as well as chemotherapy sensitivity in HCC cells were investigated by gain- and loss-of-function analyses. Associations among hsa_circ_0088036, miR-140-3p, and KIF2A were validated by real-time PCR, miRNA pull-down assay, dual-luciferase reporter assay, and western blot. Furthermore, a rescue experiment using KIF2A overexpression was performed to evaluate the regulatory mechanism of hsa_circ_0088036 in HCC cells. Additionally, the effect and mechanism of hsa_circ_0088036 were confirmed in a xenograft mouse model.
Hsa_circ_0088036 was highly expressed in HCC tissues and cells, with even higher expression in oxaliplatin-resistant cells. This expression was positively correlated with tumor size and TNM stage of the patients. Overexpression of hsa_circ_0088036 promoted the proliferation and invasion of HCC cells, while silencing mediated the opposite effects. Meanwhile, knockdown of hsa_circ_0088036 enhanced chemotherapy sensitivity, including oxaliplatin, doxorubicin, and sorafenib, in HCC cells. Furthermore, hsa_circ_0088036 silencing inhibited tumor growth and increased oxaliplatin sensitivity in vivo. Mechanically, hsa_circ_0088036 functioned via the miR-140-3p/KIF2A axis with the activation of PI3K/Akt and Notch signaling pathways.
Hsa_circ_0088036 promoted HCC tumorigenesis and chemotherapy resistance by activating the PI3K/Akt and Notch pathways through regulating miR-140-3p/KIF2A signaling. Thus, hsa_circ_0088036 may be a potential therapeutic target in chemotherapy-resistant HCC.
Wang Z
，Wang L
，Yin G
，Li H
，Zhang R
，Feng Y
，Chang W
... -
《-》
PIWIL genes in hepatocellular carcinoma: a multi-omics approach uncovering dysregulated expression and ceRNA networks in mice.
This multi-omics study delves into the expression patterns of PIWIL genes and their correlation with hepatocellular carcinoma (HCC) progression, utilizing whole transcriptome sequencing, bioinformatics, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) in mice. We identified differential expression levels of PIWIL genes between HCC and control tissues and analyzed their roles within the competing endogenous RNA (ceRNA) network related to regulatory non-coding RNA-mediated gene silencing (RNGS). Our findings showed that Piwil1 and Piwil4 were overexpressed while Piwil2 is underexpressed. As ceRNAs, specific lncRNAs, including Pvt1, Gas5, and BGIGI10090_38749, might sponge up miR-351-5p and miR-31-5p, promoting Piwil1 and Piwil4 expression, while miR-133b-3p, lacking ceRNA sponge absorption, continues to inhibit Piwil2. Through their interactions with PPI proteins encoded by RNGS genes, especially Dhx9, Drosha, Mov10, and Tdrd1, PIWI family members might play a multifaceted role in regulating gene expression and metabolic processes, thereby involving the development and progression of HCC. These interactions within the PPI network could influence the stability and activity of PIWIL proteins and contribute to the overall regulation of gene expression and HCC progression. In the RNGS, a diverse array of miRNAs, genes, lncRNAs, circRNAs, and pseudogenes have been observed, which are suggested to intricately interplay, potentially weaving a complex ceRNA regulatory network. Abnormally expressed miRNA-targeted genes in RNGS are associated with key biological processes, such as lipid metabolism and immune responses, crucial for tumor cell survival, and processes supporting tumor growth and invasion, like translation and cytoskeleton organization. This regulation is reflected in distinct KEGG pathways for downregulated and upregulated targets, highlighting the dualistic role of PIWIL genes in modulating HCC progression. The study concludes that PIWI family members have a correlation with HCC progression and play divergent roles in the pathogenesis, with overexpression of the Piwil1 and Piwil4 potentially promoting HCC progression and underexpression of Piwil2 likely suppressing tumor development. The ceRNA mechanism and PPI network are crucial in regulating the expression and function of PIWIL genes, respectively. The intricate ceRNA network potentially regulates the expression of miRNA-targeted genes in RNGS, which might be crucial for tumor survival and promotion, with impacts on immune responses and cell growth based on enriching results of dysregulated miRNA-targeted genes in HCC. By shedding light on the molecular intricacies of HCC, this multi-omics study underscores the pivotal roles of epigenetic regulations, especially the influence of PIWI family genes with other genes and ncRNAs in the RNGS process in HCC pathology. The findings offer valuable insights into the molecular mechanisms underpinning HCC, which may inform future research into potential targets for therapeutic intervention. The future research could benefit from integrating a diverse range of methodologies to further elucidate the roles of PIWIL genes in HCC progression, building upon the findings presented here.
Huang H
，Lu R
，Peng S
，Huang S
，Mo Y
，Li G
... -
《-》
ResearchGate
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钛学术
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