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.