Background

Hepatocellular carcinoma (HCC), a major type of liver cancer, ranks fourth in global incidence and third in mortality among malignant tumors [1]. In the past decade, despite notable advancements in novel drugs and therapies within the field of liver cancer treatment, along with progress in concepts such as early screening, integrated prevention, and collaboration treatment, the overall prognosis for liver cancer remains dismal [2]. The 5-year overall survival rate is only 12.1%, with merely 30% of patients having the opportunity for surgical resection [3]. Previous studies have indicated that tumor recurrence, metastasis, and drug resistance were the major causes of poor prognosis in HCC patients [4]. Therefore, further exploring the molecular mechanisms that participate in HCC development and progression would be useful for identifying novel drug targets.

HCC is among the most hypoxic malignancies, particularly within areas of tumor necrosis [5]. Moreover, treatments for HCC, such as transarterial chemoembolization that restricts blood supply to inhibit tumor growth, or tyrosine kinase inhibitors that reduce angiogenesis by inhibiting various kinase targets, can further aggravate intratumoral hypoxia [6,7,8]. Many studies revealed that within HCC tissues, the expression levels of hypoxia-inducible factors (such as HIF-1α, HIF-2α) or their target genes (GLUT1, LDHA, CA9, SLC7A1) are significantly elevated in comparison to non-tumorous liver tissue. Moreover, this elevated expression was linked to tumor recurrence, metastasis, and reduced patient survival rates [9, 10]. Functional research demonstrated that the signaling cascade of HIF molecules was involved in HCC cell proliferation, angiogenesis, invasion, and metastasis [11, 34]. Certainly, further experimental validation is needed to confirm this hypothesis.

Polyamines were essential for cell proliferation and survival, and both the growth of tumor cells and tumor progression require elevated levels of polyamines [35]. Inhibiting polyamine metabolic processes or reducing polyamine metabolic products can exert anti-tumor effects [36]. ODC1 is a rate-limiting enzyme in the downstream polyamine biosynthetic pathway [37]. In liver cancer, the expression and activity of ODC1 were elevated compared to normal tissues [29]. Difluoromethylornithine is a highly effective and specific inhibitor of ODC1 [38] and its treatment resulted in intracellular polyamine depletion, cell cycle arrest [39], thereby inhibiting tumor cell growth. Considering the significant decrease in the expression of c-Myc and ODC1 following HIGD1A silencing in HCC cells, it suggested that the intracellular polyamine metabolic pathway was inhibited, leading to a reduction in polyamine products. This inhibition consequently suppressed HCC cell proliferation and other phenotypes. Based on the above observation, we speculated that the polyamine metabolic products might serve as the effector molecules through which HIGD1A regulated the phenotypes of HCC cells. Therefore, our results further confirmed the proposed strategy that targets c-Myc and ODC1 in HCC treatment.

Conclusions

Current anti-tumor therapies for HCC remain unsatisfactory, predominantly due to their limited efficacy in blocking the high rates of recurrence and metastasis. Our study has revealed that targeted modulation of HIGD1A yields a notable inhibition to the proliferative, migratory, and invasive capacities of HCC cells. This effect is associated with polyamine levels regulated by the c-Myc–ODC1 interplay. Importantly, our study reveals the discrepancies in HIGD1A expressions and functionalities between HCC cells and their normal counterparts. This discernment helps us to identify the underlying mechanisms driving HCC tumorigenesis. Moreover, it implies a promising target for HCC therapeutic intervention, suggesting that the development of HIGD1A inhibitors could be potentially used for the treatment of liver cancer.