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.