Introduction
Annually, hepatocellular carcinoma (HCC) manifests globally with an
incidence exceeding 850,000 cases [1]. This malignancy ranks as the
second primary oncogenic cause of mortality, and its prevalence is
escalating [2]. HCC is clinically characterized by profound
cachexia, debilitating fatigue, icterus, extensive tissue infiltration,
and systemic metabolic dysregulation, all of which significantly impair
patient prognosis. The armamentarium for HCC management includes
surgical resection, hepatic arterial chemoembolization, vascular
ligation, cryoablation, thermal ablation via radiofrequency or
microwave, laser therapy, along with systemic chemotherapeutics and
ionizing radiation [3-5]. Despite these interventions, the
recurrence rate and resistance to therapy in HCC remain considerable
clinical impediments. Therefore, probing into the molecular etiologies
of hepatic oncogenesis and its progression is imperative for enhancing
diagnostic accuracy, therapeutic precision, and overall disease
outcomes.
MicroRNAs (miRNAs) are a subclass of endogenous non-coding RNAs that
orchestrate post-transcriptional gene regulation, either by repressing
translation or expediting the degradation of their target mRNAs [6,
7]. miR-205-3p, initially identified through comparative genomic
MiRscan analyses within conserved sequences between murine and the
red-finned oriental dolphin [8]; , has been corroborated in human
pathological investigations [9]. Its differential expression
profiles in various neoplasms suggest a pivotal role in tumorigenesis
and cancer progression. Diminished miR-205-3p expression characterizes
certain malignancies such as prostate [10] and breast cancer
[11] while an upregulation is documented in pathologies including
non-small cell lung carcinoma [12], melanoma[13], and head and
neck squamous carcinoma (HNSC) [14]. denoting a potential oncogenic
inducer in a tissue-specific context. Specifically, in NSCLC, miR-205-3p
has been demonstrated to instigate oncogenic pathways by modulating the
Akt signaling cascade through targeted inhibition of PHLPP2 [15].
Moreover, the miR-205-mediated silencing of PTEN has been linked to
enhanced neoplastic cell proliferation in endometrial carcinomas
[16]. These cumulative research findings emphasize the oncogenic
facilitation by miR-205-3p. Nonetheless, its explicit mechanistic role
and the pathways through which it advances HCC pathophysiology require
further elucidation.
Endoglin, commonly designated as CD105, is a membrane glycoprotein
prominently expressed on the surface of vascular endothelial cells. This
protein critically engages in the binding of transforming growth
factor-beta (TGF-β), playing a pivotal role in angiogenesis,
particularly within the context of tumor neovascularization. CD105 is
intricately associated with regulatory pathways that govern cell
proliferation.[17]. While endoglin exhibits minimal expression in
most normal tissues, its presence is pronounced in the vasculature of
the umbilical cord, underscoring its significance in angiogenesis. This
restricted expression profile renders CD105 a salient marker for the
identification and characterization of tumor-associated vascular
endothelial cells [18, 19]. Furthermore, a positive correlation
exists between CD105 expression and the proliferation markers Cyclin A
and Ki-67 within the endothelial cells of the tumor vasculature,
suggesting that CD105 expression is indicative of cellular proliferative
status [20].
Existing in a dimeric form, the Histidine triad nucleotide-binding
protein 1 (HINT1) is a purine nucleotide-binding protein and is a part
of the ancient HIT superfamily. Through the mouse knockout technique,
Tao et al [21] first discovered that the HINT1 gene may exert tumor
suppressive effects. In addition, Li et al [22] discovered a
substantially higher probability of spontaneous tumorigenesis in
HINT1-deficient mice than wild-type mice by feeding HINT1 knockout mice
for 2 to 3 years. Existing studies indicate that HINT1 protein exerts
its tumor growth inhibitory effects by suppressing tumor cell growth,
promoting apoptosis, and affecting tumor cell signaling; nevertheless,
whether HINT1 can be regulated at the transcriptional level in liver
cancer remains unclear.
Prior investigations have suggested that the progression of
hepatocellular carcinoma (HCC) may be modulated by the interplay between
miR-205-3p and Histidine triad nucleotide-binding protein 1 (HINT1);
however, the intricacies of their interaction in the regulatory
landscape of hepatic oncogenesis remain ambiguous. In this study, we
employed flow cytometry, terminal deoxynucleotidyl transferase dUTP nick
end labeling (TUNEL), and
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
assays to delineate the expression dynamics of miR-205-3p in HCC and to
elucidate its biological implications. Concomitantly, luciferase
reporter assays were conducted to verify HINT1 as a putative target in
the miR-205-3p regulatory axis. We also examined the correlation between
HINT1 protein levels and tumor vascular endothelial cells, providing an
analysis of the influence of HINT1 on the proliferation of these cells.
Our findings present novel perspectives for the therapeutic targeting of
HCC.