Zhan Yang’s research while affiliated with Hebei Medical University and other places

Background Cuproptosis is a newly discovered programmed cell death dependent on mitochondrial respiratory disorder induced by copper overload. Pyruvate dehydrogenase E1 subunit beta (PDHB) is one of the cuproptosis genesand is a nuclear-encoded pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl coenzyme A. However, the mechanism of PDHB in clear cell renal cell carcinoma (ccRCC) remains unclear. Methods We used data from TCGA and GEO to assess the expression of PDHB in normal and tumor tissues. We further analyzed the relationship between PDHB and somatic mutations and immune infiltration. Finally, we preliminarily explored the impact of PDHB on ccRCC. Results The expression level of PDHB was lower in tumor tissue compared with normal tissue. Meanwhile, the expression level of PDHB was also lower in high-grade tumors than low-grade tumors. PDHB is positively correlated with prognosis in ccRCC. Furthermore, PDHB may be associated with decreased risk of VHL, PBRM1 and KDM5C mutations. In 786-O cells, copper chloride could promote the expression of cuproptosis genes (DLAT, PDHB and FDX1) and inhibit cell growth. Last but not least, we found that PDHB could inhibit the proliferation and migration of ccRCC cells. Conclusion Our results demonstrated that PDHB could inhibit the proliferation, migration and invasion in ccRCC cells, which might be a prognostic predictor of ccRCC. Targeting this molecular might provide a new therapeutic strategy for patients with advanced ccRCC.

Background: To develop a comprehensive model for predicting disease-free survival (DFS) in patients with localized clear cell renal cell carcinoma (ccRCC). Methods: A retrospective analysis of 612 patients was performed between 2010 and 2015.The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to identify significant predictors. Furthermore, the multivariate Cox regression analysis was performed to reconfirm risk factors, then the prognosis model was constructed. The Harrell’s concordance index (C-index) was conducted to assess the model’s accuracy for predicting DFS in localized ccRCC. Results: The lymphocyte-to-monocyte ratio (LMR) (HR: 1.04, P = 0.009), the Mayo Clinic stage, size, grade, and necrosis score (SSIGN) (HR: 1.36, P < 0.001) and Mayo adhesive probability score (MAPS) (HR: 1.99, P＜0.001) were the significant risk factors screened by LASSO Cox regression and reconfirmed by multivariate Cox regression analysis in 44 variables. The LMR-SSIGN-MAPS model was constructed by combining the LMR, SSIGN, and MAPS. In the training and validation cohorts, the Harrell’s C-index was larger for the LMR-SSIGN-MAPS model (0.854, 0.848) than the SSIGN score (0.782, 0.772). The Kaplan-Meier survival analysis demonstrated the significant association between higher LMR-SSIGN-MAPS score and poorer DFS (P < 0.001) in the overall cohorts. Conclusions: The LMR-SSIGN-MAPS model which consists of preoperative inflammation biomarkers, perinephric adipose tissue image-based scoring system, and pathological features showed the strengths of easy-to-use and high predictability and might be also used as a promising prognosis model in predicting DFS for patients with localized ccRCC.

Early clinical studies indicated that estrogen receptor beta (ERβ) might play key roles to impact the progression of clear cell renal cell carcinoma (ccRCC). The detailed molecular mechanisms, however, remain unclear. Here, we found ERβ could increase the cancer stem cell (CSC) population via altering the circPHACTR4/miR‐34b‐5p/c‐Myc signaling. Mechanism dissection revealed that ERβ could suppress circular RNA PHACTR4 (circPHACTR4) expression via direct binding to the estrogen response elements (EREs) on the 5′ promoter region of its host gene, phosphatase and actin regulator 4 (PHACTR4) to decrease miR‐34b‐5p expression. The decreased miRNA‐34b‐5p could then increase c‐Myc mRNA translation via targeting its 3′ untranslated region (3′ UTR). The in vivo mouse model with subcutaneous xenografts of ccRCC cells also validated the in vitro data. Importantly, analysis results from ccRCC TCGA database and our clinical data further confirmed the above in vitro/in vivo data. Together, these results suggest that ERβ may increase CSC population in ccRCC via altering ERβ/circPHACTR4/miR‐34b‐5p/c‐Myc signaling and that targeting this newly identified signal pathway may help physicians to better suppress ccRCC progression.

Introduction: Laparoendoscopic single-site adrenalectomy (LESSA) has the advantages of early recovery and better cosmetic appearance. However, there are still debates on the efficacy and safety of LESSA and conventional laparoscopic adrenalectomy (CLA). Aim: To reevaluate the efficacy and safety of LESSA vs CLA for adrenal lesions. Material and methods: A systematic literature research of PubMed, Ovid, Scopus (up to February 2021), and citation lists was performed to identify eligible studies. All studies comparing LESSA versus CLA were included. Data were analyzed using the RevMan 5.4 software. Results: Overall, eighteen studies including 1307 patients (LESSA 520; CLA 787) were included. LESSA was associated with smaller mean tumor size (weighted mean difference (WMD) = 0.53 cm, 95% CI: -0.81 to -0.24; p < 0.001). The operative time for LESSA was longer than CLA (WMD = 13.86 min, 95% CI: 4.43 to 23.30; p = 0.004). LESSA had a better visual analog scale (VAS) score (WMD = -0.56, 95% CI: -1.01 to -0.11; p = 0.02), shorter return to diet time (WMD = -0.27 days, 95% CI: -0.52 to -0.03; p = 0.03), shorter length of hospital stay (WMD = -0.56 days, 95% CI: -1.01 to -0.11; p = 0.01), and comparable postoperative complications (OR = 0.98, 95% CI: 0.56 to 1.70; p = 0.93). The wound size of LESSA was definitely smaller (WMD = -2.72 cm, 95% CI: -3.50 to -1.94; p < 0.001). The subgroup analysis of studies via the transperitoneal approach showed reasonable results. Conclusions: LESSA is significantly better in terms of postoperative pain, time to diet, length of hospital stay and wound size, but the operative time is significantly longer.

Purpose The study aims to provide a comprehensive account of the association of five MDM4 gene polymorphisms (rs1380576, rs1563828, rs10900598, rs11801299, and rs4245739) with susceptibility to cancer. Methods A literature search for eligible candidate gene studies published before 27 February 2021 was conducted in PubMed, Medline and Web of Science. The following combinations of main keywords were used: (MDM4 OR MDMX OR HDMX OR mouse double minute 4 homolog) AND (polymorphism OR mutation OR variation OR SNP OR genotype) AND (cancer OR tumor OR neoplasm OR malignancy OR carcinoma OR adenocarcinoma). Potential sources of heterogeneity were sought out via meta-regression, subgroup and sensitivity analysis. Results Overall, a total of 15 articles with 21,365 cases and 29,280 controls for five polymorphisms of the MDM4 gene were enrolled. In the stratified analysis of rs1380576, we found that Asians might have less susceptibility to cancer. We found that rs4245739 was correlated with a decreased risk of cancer for Asians and breast cancer susceptibility. However, for other polymorphisms, the results showed no significant association with cancer risk. Conclusion MDM4 rs1380576 polymorphism is negatively associated with the risk of cancer in the Asian population. MDM4 rs4245739 polymorphism is inversely associated with cancer risk for Asians and breast cancer susceptibility.

Introduction: Due to more complex anatomical features, right laparoscopic adrenalectomy (RLA) could be more challenging than left laparoscopic adrenalectomy (LLA). However, this opinion remains elusive. Aim: To evaluate the perioperative and postoperative outcomes of RLA versus LLA. Material and methods: A systematic literature research of the PubMed, Ovid, Scopus databases (up to March 2021) and citation lists were performed to identify eligible studies. All studies comparing RLA versus LLA were included. Data were analysed using RevMan 5.4 software. Results: Overall, 5 studies including 780 patients (RLA 361; LLA 419) were included. The operative time was similar in both groups (WMD -9.38 min, 95% CI: -21.04 to 2.28; p = 0.11). Compared with LLA, RLA showed greater volume of estimated blood loss (EBL) (WMD 13.82 ml, 95% CI: 3.77, 23.88; p = 0.007) and higher conversion rate (OR = 3.45, 95% CI: 1.12 to 10.57; p = 0.03). RLA had comparable complications (OR = 0.88, 95% CI: 0.44 to 1.76; p = 0.71), Clavien Dindo score ≥ 3 complications (OR = 0.38, 95% CI: 0.09 to 1.65; p = 0.20), and length of hospital stay (WMD -0.07 days, 95% CI: -0.35 to 0.21; p = 0.61). The transperitoneal approach analysis showed consistent results. Conclusions: RLA is associated with a higher risk of bleeding and higher conversion rate.

Introduction: The application of robotic adrenalectomy (RA) has been increasing. However, there is still controversy about whether RA is more feasible than laparoscopic adrenalectomy (LA) for pheochromocytoma (PHEO). Aim: To evaluate the efficacy and safety of RA vs. LA for PHEO. Material and methods: A literature search of the PubMed, Ovid, and Scopus databases was performed to identify eligible studies up to April 2021. All studies comparing RA versus LA for PHEO were included. Data were analysed using the Cochrane Collaboration's Review Manager (RevMan) 5.4 software. Results: Overall, 4 studies including 386 patients (RA 155; LA 231) were included. RA might have larger tumour size (WMD = 0.72 cm, 95% CI: 0.31 to 1.13; p < 0.001). There were no statistically significant differences in operative time (WMD = -12.49 min, 95% CI: -29.50 to 4.52; p = 0.15), estimated blood loss (EBL) (WMD = -28.48 ml, 95% CI: -58.92, 1.95; p = 0.07), transfusion rate (OR = 0.70, 95% CI: 0.07 to 7.07; p = 0.77), or conversion rate (OR = 0.44, 95% CI: 0.07 to 2.88; p = 0.39). There were no significant differences between the 2 groups in terms of postoperative complications (OR = 1.06, 95% CI: 0.62 to 1.82; p = 0.84) and Clavien Dindo score ≥ 3 complications (OR = 1.15, 95% CI: 0.39 to 3.41; p = 0.80). Patients from the RA group could benefit from shorter length of hospital stay (WMD = -0.51 days, 95% CI -0.91 to -0.12; p = 0.01). Conclusions: RA is a feasible, safe, and comparable treatment option for PHEO.

Background: STAT5 plays an important role in the transformation of hematopoietic cells by BCR-ABL. However, the downstream target genes activated by STAT5 in chronic myeloid leukemia (CML) cells remain largely unclear. Here, we investigated the mechanistic functional relationship between STAT5A-regulated microRNA and CML cell apoptosis. Methods: The expression of USP15, Caspase-6, STAT5A-regulated miR-202-5p and STAT5A was detected by qRT-PCR and Western blotting in CML cell lines and PBMCs of CML patients. Cell apoptosis was evaluated by flow cytometry. Both gain- and loss-of-function experiments were used to investigate the roles of USP15, miR-202-5p and STAT5A in CML. Luciferase reporter assay detected the effect of miR-202-5p on USP15 expression. Xenograft animal model was used to test the effect of anti-miR-202-5p and pimozide on K562 cell xenograft growth. Results: USP15 expression was significantly downregulated in CML cell lines and PBMCs of CML patients. Depletion of USP15 increased, whereas overexpression of USP15 reduced the resistance of CML cells to Imatinib. Further, decreased deubiquitinating activity of USP15 by USP15 downregulation led to reduced caspase-6 level, thus attenuating CML cell apoptosis. Mechanistically, miR-202-5p was upregulated in K562G cells and negatively regulated USP15 expression by directly targeting USP15 3'-UTR. Correspondingly, upregulation of miR-202-5p enhanced the resistance of CML cells to Imatinib by inhibiting cell apoptosis. Importantly, STAT5A was upregulated in CML cells and directly activated miR-202-5p transcription by binding to the pre-miR-202 promoter. Pimozide induced CML cell apoptosis and significantly reduced K562 cell xenograft growth in vivo by blocking STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis. Conclusions: we provide the first evidence that de-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses the apoptosis of CML cells, targeting this pathway might be a promising therapeutic approach for the treatment of CML.

Increased activity of PI3K/AKT/mTOR pathway has been observed in chronic myeloid leukemia (CML). Morin, a kind of flavonoid, exhibits a significant anticancer activity by suppressing the PI3K/AKT signaling pathway. However, the effect of morin on CML and its underlying mechanisms are poorly understood. Here, we found that morin dose-dependently inhibited the proliferation of CML cell lines K562 and KCL22 and induced their apoptosis, with a significant increase in cell apoptosis upon exposure of cells to 50 μM morin. Moreover, morin significantly reduced CML xenograft growth in nude mice. Mechanically, morin attenuated phosphorylated AKT level by upregulating PTEN expression, thus leading to the inhibition of AKT signaling. Knockdown of PTEN by its si-RNA completely abrogated morin-induced cell apoptosis, indicating that PTEN mediates the inductive effect of morin on CML cell apoptosis. More importantly, we found that miR-188-5p was significantly upregulated in CML patients and CML cell lines. Treating CML cells with morin markedly downregulated miR-188-5p expression level. Further, we demonstrated that miR-188-5p repressed PTEN expression by directly targeting its 3′-UTR. miR-188-5p downregulation induced by morin enhanced CML cell apoptosis by relieving miR-188-5p repression of PTEN expression. In summary, morin exerts significant anticancer efficacy in CML by regulating miR-188-5p/PTEN axis and thus repressing the PI3K/AKT signaling.

Background Docetaxel-based chemotherapy failure in advanced prostate carcinoma has partly been attributed to the resistance of prostate cancer (PC) cells to docetaxel-induced apoptosis. Hence, there is an urgent need to identify mechanisms of docetaxel chemoresistance and to develop new combination therapies. MethodsmiR-193a-5p level was evaluated by qPCR in prostate tissues and cell lines, and its expression in the tissues was also examined by in situ hybridization. PC cell line (PC3 cell) was transfected with miR-193a-5p mimic or its inhibitor, and then cell apoptosis and the expression of its downstream genes Bach2 and HO-1 were detected by TUNEL staining and Western blotting. Luciferase reporter assay was used to detect the effect of miR-193a-5p and Bach2 on HO-1 expression. Xenograft animal model was used to test the effect of miR-193a-5p and docetaxel on PC3 xenograft growth. ResultsmiR-193a-5p was upregulated in PC tissues and PC cell lines, with significant suppression of PC3 cell apoptosis induced by oxidative stress. Mechanistically, miR-193a-5p suppressed the expression of Bach2, a repressor of the HO-1 gene, by directly targeting the Bach2 mRNA 3′-UTR. Docetaxel treatment modestly decreased Bach2 expression and increased HO-1 level in PC3 cells, whereas a modest increase of HO-1 facilitated docetaxel-induced apoptosis. Notably, docetaxel-induced miR-193a-5p upregulation, which in turn inhibits Bach2 expression and thus relieves Bach2 repression of HO-1 expression, partly counteracted docetaxel-induced apoptosis, as evidenced by the increased Bcl-2 and decreased Bax expression. Accordingly, silencing of miR-193a-5p enhanced sensitization of PC3 cells to docetaxel-induced apoptosis. Finally, depletion of miR-193a-5p significantly reduced PC xenograft growth in vivo. Conclusions Silencing of miR-193a-5p or blockade of the miR-193a-5p-Bach2-HO-1 pathway may be a novel therapeutic approach for castration-resistant PC.