Discussion
Previous research has examined the potential impact of abnormal miRNA expression levels on the development of tumors. [31-33]. Given the intimate connection between miRNAs and tumors, mounting data illustrate that the management of miRNA expression could potentially introduce a new and effective approach to tumor therapy. [34]. Our data show that miR-205-3p downregulation remarkably suppresses vascular endothelial cell proliferation and survival in liver cancer. It also enhances apoptosis by focusing on the tumor suppressor HINT1.
miR-205-3p, which is encoded by the LOC642587 locus in the second intron of chromosome 1, is associated with the onset and progression of different types of cancer [35-37]. Past research suggests that both tumor suppression and oncogenic activity may be attributed to miR-205-3p. Overexpression of miR-205-3p inhibits carcinogenesis substantially because of its role as a tumor suppressor [38]. Furthermore, the expression levels of miR-205-3p are associated with the existence of melanoma tissue. Downregulation of miR-205-3p leads to a worse clinical prognosis [39, 40]. On the other hand, various types of cancer may be contributed by the miR-205-3p. For instance, Niu et al [41] observed an upregulation of miR-205-3p in ovarian cancer, its upregulation directly correlating with advanced disease stages. Targets in distinct tumor microenvironments may account for the various functions of miR-205-3p. As such, this study set out to compare miR-205-3p expression in patients with liver cancer and adjoining non-cancerous healthy tissues. We initially found markedly elevated miR-205-3p levels in liver cancer vascular endothelial cells compared to normal hepatic vascular endothelial cell tissue. Moreover, miR-205-3p exhibits a high expression state in advanced (III and V) clinical patients. In contrast, utilizing miR-205-3p inhibitors to inhibit miR-205-3p resulted in enhanced apoptosis and reduced tumor size in HepG2 and HepB3 cells in mice. In conclusion, the current findings suggest that miR-205-3p modulates liver cancer tumorigenesis and hastens its progression.
Investigating the potential mechanisms underpinning miR-205-3p’s promotion of tumor growth, this study focused on HINT1 as a possible direct target in liver cancer vascular endothelial cells. We observed HINT1 expression alterations by introducing a miR-205-3p inhibitor into both liver cancer and healthy hepatic vascular endothelial cells. Our findings highlighted a significant discrepancy in HINT1 expression between these two types of cells. Furthermore, the miR-205-3p inhibitor notably augmented HINT1 protein and mRNA expression across different cellular and tissue models compared to their respective controls. This consolidates the idea that miR-205-3p binds to the 3’-UTR region of HINT1, aligning with the outcomes from the luciferase reporter assay. However, this study is not devoid of limitations. While studies suggest that miR-205-3p can influence liver cancer progression by targeting HINT1, further exploration is needed to understand how HINT1 modulates cancer cell behavior. Additionally, the expression of HINT1 in vascular endothelial cells in liver cancer and its link to clinical features and the prognosis of liver cancer patients is still uncertain because of the small number of clinical samples available. Future research should delve into the potential roles of HINT1 in liver cancer. Despite these constraints, our study contributes to the expanding knowledge of liver cancer.
The prediction of our group through high-throughput sequencing results shows that the target genes that may bind to miR-205-3p are PLAC8, LRRQ4, and CLL15.Currently, it has been shown that PLAC8 can promote the proliferation of hepatocellular carcinoma cells by down-regulating and enhancing the Wnt/β-catenin signaling pathway [42]. And LRRIQ4 is a gene in the human genome that belongs to the protein family of Leucine-rich repeats (LRRs). Some studies have found that the Terc gene cluster (LRRIQ4) has an effect on hepatic telomere length (aTL) using a mouse model, which in turn may affect liver growth [43]. CCL15 belongs to the CC chemokine family, and it is moreover a serum biomarker and an independent predictor of hepatocellular carcinoma survival [44, 45], and it has been demonstrated that CCL15 can pass through the CCR1 axis for hepatocellular carcinoma metastasis [46].
In summary, our investigation revealed a notable increase in miR-205-3p levels within liver cancer vascular endothelial tissue, correlating with a less favorable prognosis for patients suffering from liver cancer. MiR-205-3p seems to have a function in driving liver cancer development by regulating HINT1. These insights demonstrate that miR-205-3p may be involved in liver cancer pathogenesis. The biological value of miR-205-3p/HINT1 interaction in liver cancer warrants additional investigation.
Acknowledgments: Not applicable.
Informed consent: All individuals in this study have given their informed consent.
Ethics approval and consent to participate: The current study received approval from the Medical Ethics Committee of Ningbo Medical Center Li Huili Hospital (approval no. KY2021PJ188).
Authors’ contributions: The experiments were conceptualized and planned by LH and MQQ. The execution of the experiments was carried out by MQQ, WMN, and XJQ. Data analysis and interpretation were performed by MQQ and WMN. The manuscript was written by WMN and subsequently revised by MQQ and LH. The authenticity of all raw data has been confirmed by MQQ, LH, and WMN. The final manuscript was read and approved by all authors.
Competing interests: The authors declare that they have no competing interests.
Funding: The Project of Zhejiang Medical and Health Platform Plan (No.2022KY1079) provided financial support for this research.
Availability of data and materials: The datasets utilized and/or examined in the present study can be made accessible by the corresponding author upon a reasonable request.
Patient consent for publication: Not applicable.