ABSTRACT
BACKGROUND: The incidence and mortality of liver cancer are among the highest of all malignant tumors in China. The high recurrence rate after conventional hepatectomy is worrying. There is a lack of effective prognostic indicators for liver cancer. AIM: To explore the clinical significance of preoperative serum oxidative stress and serum uric acid (UA) levels in hepatitis B-related liver cancer. METHODS: The medical records of 110 hepatitis B-related liver cancer patients who underwent hepatectomy in Gansu Provincial Hospital were retrospectively analyzed. Recurrence in patients within 3 years after surgery was determined. The logistic regression model and Pearson or Spearman correlation were used to analyze the correlation between oxidative stress level and UA, and the recurrence of hepatitis B-related liver cancer. RESULTS: Compared with the non-recurrence group, the levels of superoxide dismutase (SOD) and glutathione (GSH) in the recurrence group were lower and the levels of malondialdehyde (MDA) and UA were higher (all P < 0.05). UA, SOD, MDA, and GSH were risk factors for postoperative recurrence in hepatitis B-related liver cancer patients (P < 0.05). UA was positively correlated with MDA (r = 0.395, P < 0.001) and negatively correlated with GSH (r = -0.204, P = 0.032). The area under the receiver operating characteristic curve (AUC) of SOD, MDA, GSH, and UA in predicting the prognosis was 0.276, 0.910, 0.199, and 0.784, respectively (all P < 0.001). CONCLUSION: The preoperative serum SOD, GSH, MDA, and UA levels had significant predictive effects on postoperative recurrence of hepatitis B-related liver cancer.
ABSTRACT
Although arsenic trioxide (ATO) shows a strong anti-tumor effect in the treatment of acute promyelocytic leukemia, it does not benefit patients with hepatocellular carcinoma (HCC). Thus, combination therapy is proposed to enhance the efficacy of ATO. Parthenolide (PTL), a natural compound, selectively eradicates cancer cells and cancer stem cells with no toxicity to normal cells. In this study, we chose PTL and ATO in combination and found that nontoxic dosage of PTL and ATO co-treatment can synergistically inhibit the in vitro and in vivo proliferation activity of HCC cells through suppressing stemness and self-renewal ability and inducing mitochondria-dependent apoptosis. More importantly, USP7-HUWE1-p53 pathway is involved in PTL enhancing ATO-induced apoptosis of HCC cell lines. Meanwhile, accompanied by induction of apoptosis, PTL and ATO evoke autophagic activity via inhibiting PI3K/Akt/mTOR pathway, and consciously controlling autophagy can improve the anti-HCC efficacy of a combination of PTL and ATO. In short, our conclusion represents a novel promising approach to the treatment of HCC.
ABSTRACT
Helicobacter pylori (H. pylori)-derived vacuolating cytotoxin A (VacA) causes damage to various organelles, including mitochondria, and induces autophagy and cell death. However, it is unknown whether VacA-induced mitochondrial damage can develop into mitophagy. In this study, we found that H. pylori, H. pylori culture filtrate (HPCF), and VacA could activate autophagy in a gastric epithelial cell line (GES-1). VacA-caused mitochondrial depolarization retards the import of PINK1 into the damaged mitochondria and evokes mitophagy. And, among mass spectrometry (LC-MS/MS) identified 25 mitochondrial proteins bound with VacA, Tom20, Tom40, and Tom70, TOM complexes responsible for PINK1 import, were further identified as having the ability to bind VacA in vitro using pull-down assay, co-immunoprecipitation, and protein-protein docking. Additionally, we found that the cell membrane protein STOM and the mitochondrial inner membrane protein PGAM5 also interacted with VacA. These findings suggest that VacA captured by STOM forms endosomes to enter cells and target mitochondria. Then, VacA is transported into the mitochondrial membrane space through the TOM complexes, and PGAM5 aids in inserting VacA into the inner mitochondrial membrane to destroy the membrane potential, which promotes PINK1 accumulation and Parkin recruitment to induce mitophagy. This study helps us understand VacA entering mitochondria to induce the mitophagy process.
ABSTRACT
Although many drugs that targeted the specific features of leukemia stem cells (LSCs) have substantial application in the clinical treatment of leukemia, the LSCs relapsed and caused drug-resistant leukemia. Therefore, it is necessary to identify the unique features of LSCs in relapsing and drug-resistant leukemia and also to explore the drugs that directed at these features. Our clinical data have indicated that relapsed patients with acute myeloid leukemia have more abundant proportion of LSCs with enhanced breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) expression when compared to the untreated patients. The results showed that compared with LSCs derived from sensitive K562 cells, LSCs from drug-resistant K562/ADM cells have much higher chemotherapeutic resistance, and so we termed these cells as "drug-resistant LSCs". Subsequently, aberrant activation of NF-κB pathway in drug-resistant LSCs was further using gene chip analysis. Also, parthenolide (PTL), which is a specific NF-κB inhibitor, effectively eliminated drug-resistant LSCs and enhanced the sensitivity of K562/ADM cells to doxorubicin-induced apoptosis by down-regulating NF-κB pathway-mediated P-gp expression. These findings make the research area of LSCs more abundant and provide a potential therapeutic strategy for the treatment of refractory and relapsed leukemia.
