Jingtao Zhong

Purpose: This study evaluated the hepatoprotective effects and safety profile of donafenib combined with transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC) through analysis of albumin-bilirubin (ALBI) score modifications.Patients and methods: We enrolled 36 patients with unresectable HCC receiving donafenib+TACE, with or without immune checkpoint inhibitors. ALBI grades were assessed at baseline and throughout treatment, with statistical analyses examining associations between ALBI grade changes, tumor response, and survival outcomes.Results: Our prospective analysis demonstrated significant antitumor efficacy with favorable hepatic safety. The regimen achieved objective response and disease control rates of 69.4% and 91.7%, respectively, with median progression-free survival of 10.7 months and median time to response of 1.4 months, indicating rapid therapeutic onset. Hepatic function remained stable throughout treatment, with consistent ALBI grades from baseline to progression/final follow-up (−2.41 ± 0.41 vs. −2.45 ± 0.52, P=0.67). Among patients, 58.3% maintained stable hepatic function, while 25.0% improved from ALBI grade 2 to 1. Hepatic function deterioration occurred less frequently in responders than nonresponders (12.0% vs. 27.3%). ALBI grade modification emerged as a potential predictive biomarker (AUC=0.665). Patients with ALBI grade below the −0.18 threshold achieved superior clinical outcomes, including higher response rates (84.6% vs. 56.5%) and longer progression-free survival (not reached vs. 5.63 months, P=0.017). These findings establish hepatic function preservation as both a safety indicator and efficacy predictor for donafenib+TACE therapy.Conclusion: The combination of donafenib and TACE demonstrates favorable hepatic function preservation while maintaining therapeutic efficacy. ALBI grade improvement is correlated with enhanced treatment response and survival outcomes, indicating potential synergistic benefits for tumor control and hepatic function preservation.

Primary liver cancer ranks as the sixth most prevalent malignant tumor and stands as the second leading cause of cancer-related mortality globally, posing a significant threat to public health. Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Surgical resection remains the cornerstone treatment for achieving radical cure and prolonged survival in HCC patients. Contrary to Western countries, the majority of HCC patients in China present with hepatitis B virus infection and consequent liver cirrhosis, with most cases diagnosed at an intermediate or advanced stage. This complexity results in a poor prognosis. Recent advancements in local therapeutic techniques and the introduction of systemic therapies, including targeted and immunotherapy agents, have provided new avenues for both clinical and basic conversion therapy for advanced HCC. Integrating multi-dimensional local and systemic therapies, multi-modal sequential, and comprehensive multidisciplinary approaches into the management of HCC patients has demonstrated promising conversion success rates. This holistic management strategy involves combining multiple treatment modalities vertically and coordinating various disciplines horizontally. However, significant challenges remain, including the precise selection of patients eligible for conversion therapy, the optimal choice of conversion therapy regimens, and the accurate determination of surgical timing post-conversion therapy. Addressing these challenges is crucial for hepatobiliary surgeons. High-quality, randomized controlled trials are urgently needed to generate robust evidence for clinical practice. This review aims to synthesize the latest research developments both in China and internationally and examines key issues in the realm of HCC conversion therapy.

To investigate the role of pseudouridine synthase 7 (PUS7) in pancreatic cancer (PC) and explore its underlying molecular mechanisms. PUS7 role in the malignant biological function of PC cells was investigated by colony formation, EdU, flow cytometry, and transwell assays. PUS7 function on glycolysis of PC cells was determined through assessing the extracellular acidification rate and oxygen consumption rate. Besides, the potential molecular mechanism by which PUS7 affects PC was investigated via utilizing immunohistochemistry staining, western blot, qRT-PCR, and co-immunoprecipitation. Xenograft tumors were constructed using BALB/c nude mice. PUS7 was highly expressed in PC tissues. PUS7 significantly accelerated proliferation, mobility and glycolysis, but suppressed apoptosis in PC. Furthermore, PUS7 promoted the malignant biological function of PC cells by interacting anillin (ANLN). We also demonstrated that PUS7 promoted the malignant biological function of PC cells by activating the MYC pathway. PUS7 promoted PC progression via activating the MYC pathway in vivo. Our results indicated that PUS7 could promote cell proliferation, mobility and glycolysis, and inhibit apoptosis by interacting ANLN to activate the MYC pathway in PC.

Hepatocellular carcinoma (HCC) is regarded as a leading cause of cancer-related deaths, and its progression is associated with hypoxia and the induction of hypoxia-inducible factor (HIF). Meloxicam, a selective cyclooxygenase-2 (COX-2) inhibitor, induces cell death in various malignancies. However, the underlying mechanism remains to be elucidated in HCC, especially under hypoxic conditions. The alteration of COX-2 and HIF-1α oncogenicity was evaluated in HCC specimens by tissue microarray. Cell viability, angiogenesis assays, and xenografted nude mice were used to evaluate the effects of meloxicam, along with flow cytometry to detect the cell cycle, apoptosis, and mitochondrial membrane potential (ΔΨm) of HCC. qRT-PCR, Western blotting, immunofluorescence, immunohistochemistry, luciferase assay, and RNAi were carried out to determine the HIF-1α signaling affected by meloxicam. In this study, we showed that meloxicam exerts antiproliferative and antiangiogenesis efficacy in vitro and in vivo and causes disruption of mitochondrial membrane potential (ΔΨm), thus leading to caspase-dependent apoptosis under hypoxic environments. Exposure to meloxicam significantly reduced HIF-1α transcriptional activation and expression through sequestering it in the cytoplasm and accelerating degradation via increasing the von Hippel-Lindau tumor suppressor protein (pVHL) in HCC. These data demonstrated that inhibition of HIF-1α by meloxicam could suppress angiogenesis and enhance apoptosis of HCC cells. This discovery highlights that COX-2 specific inhibitors may be a promising therapy in the treatment of HCC.

The T7 peptide, an active fragment of full‑length tumstatin [the non‑collagenous 1 domain of the type IV collagen α3 chain, α3 (IV) NC1], has exhibited potential antitumor effects in several types of cancer cells. However, the mechanism underlying its action against human hepatocellular carcinoma (HCC) remains unclear. The present study aimed to investigate the role of autophagy in T7 peptide‑induced cytotoxicity in HCC cells in vitro and in vivo. The results revealed that the T7 peptide significantly reduced cell viability and induced cell cycle arrest in HCC cells. The T7 peptide induced apoptosis in HCC cells through upregulation of Bax, Fas, and Fas ligand, and through upregulation of the anti‑apoptotic protein Bcl‑2. In addition, treatment with the T7 peptide induced protective autophagy in HCC cells. Blocking autophagy by 3‑methyladenineor bafilomycin A1 enhanced T7 peptide‑induced apoptosis. Furthermore, co‑treatment with MK‑2206 (an Akt specific inhibitor) or rapamycin (an inhibitor of mTOR) enhanced T7 peptide‑induced autophagy, whereas co‑treatment with insulin (an activator of the Akt/mTOR signaling pathway) alleviated T7 peptide‑induced autophagy, which suggested that the T7 peptide may induce autophagy activation via inhibition of the Akt/mTOR signaling pathway. Taken together, the present results demonstrated that suppression of autophagy potentiated the cytotoxic effects of the T7 peptide, and suggested that the T7 peptide may serve as a potential alternative compound for HCC therapy.

Recurrence and metastasis are the two leading causes of poor prognosis in patients with hepatocellular carcinoma (HCC). Secreted clusterin (sCLU) is a stress‑induced chaperone that is overexpressed in HCC. However, the precise molecular mechanisms of sCLU in HCC invasion and migration are largely unknown. In the present study, it was indicated that downregulation of sCLU significantly alleviated invasiveness whereas overexpression of sCLU notably enhanced the number of invasive cells via mediating the expression level of MMP‑2 and E‑cadherin in Bel‑7402 and SMMC‑7721 cells. Furthermore, as an important mediator of invasiveness, sCLU may be responsible for proliferation and invasion suppression induced by meloxicam (a selective inhibitor of cyclooxygenase‑2) in HCC cells. The combination of meloxicam and CLU shRNA significantly decreased invasion in HCC cells in vitro. Furthermore, it was observed that overexpression of sCLU significantly potentiated expression of p‑AKT and MMP‑2. However, downregulation of sCLU by CLU shRNA alleviated the extent of p‑AKT. These results suggest the targeting of sCLU may be a novel therapeutic strategy against invasion and migration in HCC.

Secretory clusterin (sCLU) is overexpressed in cancer and is associated with resistance to chemotherapy in several types of cancer, including hepatocellular carcinoma (HCC). Sorafenib (SOR), a multikinase inhibitor of Raf/mitogen‑activated protein kinase kinase/extracellular signal‑regulated kinase (ERK) signaling and the receptor tyrosine kinase, is recognized as the standard therapeutic strategy for patients with advanced HCC. However, the role of sCLU in the resistance of HCC to SOR remains to be fully elucidated. In the present study, sCLU was silenced by CLU short hairpin (sh)RNA in Bel‑7402 and SMMC‑7721 cell lines, following which the cells were treated with SOR. Cell proliferation was determined using a CCK‑8 assay. Apoptosis was quantified using flow cytometry. The production of sCLU, B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X sprotein and phosphorylated (p)ERK1/2 was analyzed using western blot analysis. The results showed that sCLU was overexpressed in three HCC cell lines. The downregulation of sCLU by CLU shRNA synergistically increased SOR sensitivity in the Bel‑7402 and SMMC‑7721 cells, and potentiated SOR‑induced cell apoptosis. In addition, silencing sCLU or combination with PD98059 decreased the SOR‑induced activation of pERK1/2. These findings indicate a novel treatment strategy for HCC.

The P18 peptide is a functional fragment of pigment epithelial-derived factor (PEDF), which is an endogenic angiogenesis inhibitor. This study sought to determine the anti-angiogenic bioactivity of the P18 peptide in hepato-cellular carcinoma (HCC) and to elucidate the underlying mechanism. Xenograft tumour growth assays demonstrated the P18 peptide suppressed angiogenesis of HCC in vivo. Wound healing, Transwell and Matrigel-culture assays indicated that the P18 peptide inhibited the cell migration and tube formation of endothelial cells (ECs) in vitro. Cell viability and apoptosis assessed by Cell Counting Kit-8 (CCK-8) and flow cytometry assays suggested that the P18 peptide inhibited angiogenesis by inducing apoptosis of ECs. Angiogenesis- and signal transduction-associated molecules analysed by western blot demonstrated that the P18 peptide targets vascular endothelial cell growth factor receptor 2 (VEGFR2) on ECs. In conclusion, by inhibiting the phosphorylation of VEGFR2, the P18 peptide modulates signalling transduction between VEGF/VEGFR2 and suppresses activation of the PI3K/Akt cascades, leading to an increase in mitochondrial-mediated apoptosis and anti-angiogenic activity. This bioactivity of the P18 peptide may represent a novel therapeutic strategy for the treatment of HCC.