Bin Zhang

Bio: Bin Zhang is an academic researcher from Huazhong University of Science and Technology. The author has contributed to research in topics: Tumor progression & Cancer. The author has an hindex of 1, co-authored 4 publications receiving 4 citations.

RRM2 Regulates Sensitivity to Sunitinib and PD-1 Blockade in Renal Cancer by Stabilizing ANXA1 and Activating the AKT Pathway.

Abstract: Renal cell carcinoma (RCC) is a malignant tumor of the kidneys. Approximately 70% of RCC cases are clear cell renal cell carcinoma with von Hippel-Lindau (VHL) gene mutation and activation of the vascular endothelial growth factor (VEGF) pathway. Tyrosine kinase inhibitors (TKIs) targeting VEGF have emerged as promising agents for RCC treatment. Apart from primary resistance, acquired resistance to TKIs after initial tumor regression is common in RCC. Recently, immune checkpoint inhibition, including PD-1/PD-L1 blockade, alone or in combination with TKIs has improved the overall survival of patients with RCC. Ribonucleotide reductase subunit M2 (RRM2) has been reported in many types of cancer and has been implicated in tumor progression. However, the role of RRM2 in TKIs resistance in RCC remains unclear. In this study, the authors have demonstrated that RRM2 is upregulated in sunitinib-resistant RCC cells and patient tissues. They also find that RRM2 stabilizes ANXA1 and activates the AKT pathway independent of its ribonucleotide reductase activity, promoting sunitinib resistance in RCC. Moreover, RRM2 regulated antitumor immune responses, and knockdown of RRM2 enhance the anti-tumor efficiency of PD-1 blockade in renal cancer. Collectively, these results suggest that aberrantly expressed RRM2 may be a promising therapeutic target for RCC.

USP24-GSDMB complex promotes bladder cancer proliferation via activation of the STAT3 pathway.

Abstract: Background: Bladder cancer is the fourth and tenth most common malignancy in men and women worldwide, respectively. One of the main reasons for the unsatisfactory therapeutic control of bladder cancer is that the molecular biological mechanism of bladder cancer is complex. Gasdermin B (GSDMB) is one member of the gasdermin family and participates in the regulation of cell pyroptosis. The role of GSDMB in bladder cancer has not been studied to date. Methods: TCGA database was used to exam the clinical relevance of GSDMB. Functional assays such as MTT assay, Celigo fluorescent cell-counting assay, Annexin V-APC assay and xenografts were used to evaluate the biological role of GSDMB in bladder cancer. Mass spectrometry and immunoprecipitation were used to detect the protein interaction between GSDMB and STAT3, or GSDMB and USP24. Western blot and immunohistochemistry were used to study the relationship between USP24, GSDMB and STAT3. Results: In this study, bioinformatics analysis indicated that the mRNA expression level of GSDMB in bladder cancer tissues was higher than that in adjacent normal tissues. Then, we showed that GSDMB promoted bladder cancer progression. Furthermore, we demonstrated that GSDMB interacted with STAT3 to increase the phosphorylation of STAT3 and modulate the glucose metabolism and promote tumor growth in bladder cancer cells. Besides, we also showed that USP24 stabilized GSDMB to activate STAT3 signaling, which was blocked by the USP24 inhibitor. Conclusions: We suggested that aberrantly up-regulated GSDMB was responsible for enhancing the growth and invasion ability of bladder cancer cells. Then, we showed that GSDMB could bind to STAT3 and activate STAT3 signaling in bladder cancer. Furthermore, we also demonstrated that USP24 interacted with GSDMB and prevented GSDMB from degradation in bladder cancer cells. Therefore, the USP24/GSDMB/STAT3 axis may be a new targetable signaling pathway for bladder cancer treatment.

Smoking-associated upregulation of CBX3 suppresses ARHGAP24 expression to activate Rac1 signaling and promote tumor progression in lung adenocarcinoma.

Abstract: Although tobacco smoking is a risk factor for lung adenocarcinoma (LUAD), the mechanisms by which tobacco smoking induces LUAD development remain elusive. Histone methylation levels in human bronchial epithelial cells have been reported to increase after exposure to cigarettes. In this study, we explored the mechanisms regulating histone methylation in LUAD in response to smoking. We found that the histone H3K9 methylation reader CBX3 was upregulated in current smokers with LUAD, and that CBX3 overexpression promoted LUAD progression. Functional enrichment analyses revealed that CBX3 regulated the activation of Rho GTPases in LUAD. We also found that by forming a complex with TRIM28, TRIM24, and RBBP4, CBX3 repressed the expression of ARHGAP24 and increased the amount of active Rac1 in LUAD cells. Collectively, these results suggest that smoking associated upregulation of CBX3 promotes LUAD progression by activating the ARHGAP24/Rac1 pathway. Hence, the CBX3/ARHGAP24/Rac1 axis may represent a promising therapeutic target in smoking-induced LUAD.

UBE3A activates the NOTCH pathway and promotes esophageal cancer progression by degradation of ZNF185

Abstract: Background: Esophageal cancer is the sixth-most common fatal malignant tumor worldwide. Little is known regarding the genetic drivers that influence targeted therapy outcomes in patients with esophageal cancer. Exploring the pathogenesis of this lethal tumor could provide clues for developing appropriate therapeutic drugs. Ubiquitin-protein ligase E3A (UBE3A) reportedly promotes or suppresses various types of malignant tumors. However, the cancer-related role of UBE3A in esophageal cancer remains unclear. Methods: The relationship of UBE3A with the clinicopathological features of pancreatic tumors was bioinformatically investigated in the TCGA dataset. The protein levels of UBE3A and ZNF185 were assessed by Western blot and immunohistochemistry. The role of UBE3A and ZNF185 in esophageal cancer growth was assessed by MTS assays, colony formation assays, and experiments in mouse xenograft models. The interaction between UBE3A and ZNF185 was investigated by co-immunoprecipitation. The relationship between UBE3A, ZNF185, and NOTCH signaling pathway was explored by Western blot and quantitative real-time PCR. Results: We found that UBE3A was upregulated in patients with esophageal cancer and enhanced the cellular progression of esophageal cancer. Moreover, we found that UBE3A degraded ZNF185 in esophageal cancer. Additionally, ZNF185 suppressed the progression of esophageal cancer by inactivating the NOTCH pathway. Conclusions: These data demonstrated that aberrant expression of UBE3A led to enhanced progression of esophageal cancer through the ZNF185/NOTCH signaling axis. Therefore, UBE3A might be an ideal therapeutic candidate for esophageal cancer.

Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

Abstract: Abstract Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments.

Identification and Validation of a Ferroptosis-Related Long Non-Coding RNA (FRlncRNA) Signature to Predict Survival Outcomes and the Immune Microenvironment in Patients With Clear Cell Renal Cell Carcinoma

Abstract: Background: The incidence of clear cell renal cell carcinoma (ccRCC) is increasing worldwide, contributing to 70–85% of kidney cancer cases. Ferroptosis is a novel type of programmed cell death and could predict prognoses in cancers. Here, we developed a ferroptosis-related long non-coding RNA (FRlncRNA) signature to improve the prognostic prediction of ccRCC. Methods: The transcriptome profiles of FRlncRNAs and clinical data of ccRCC were obtained from The Cancer Genome Atlas and ICGC databases. Patients were randomly assigned to training cohorts, testing cohorts, and overall cohorts. The FRlncRNA signature was constructed by Lasso regression and Cox regression analysis, and Kaplan–Meier (K-M) analysis was used to access the prognosis of each group. The accuracy of this signature was evaluated by the receiver operating characteristic (ROC) curve. The visualization of functional enrichment was carried out by the gene set enrichment analysis (GSEA). Internal and external datasets were performed to verify the FRlncRNA signature. Results: A FRlncRNA signature comprising eight lncRNAs (AL590094.1, LINC00460, LINC00944, AC024060.1, HOXB-AS4, LINC01615, EPB41L4A-DT, and LINC01550) was identified. Patients were divided into low- and high-risk groups according to the median risk score, in which the high-risk group owned a dramatical shorter survival time than that of the low-risk group. Through ROC analysis, it was found that this signature had a greater predictive capability than traditional evaluation methods. The risk score was an independent risk factor for overall survival suggested by multivariate Cox analysis (HR = 1.065, 95%CI = 1.036–1.095, and p < 0.001). We constructed a clinically predictive nomogram based on this signature and its clinical features, which is of accurate prediction about the survival rate of patients. The GSEA showed that primary pathways were the P53 signaling pathway and tumor necrosis factor–mediated signaling pathway. The major FRlncRNAs (LINC00460, LINC00944, LINC01550, and EPB41L4A-DT) were verified with the prognosis of ccRCC in the GEPIA and K-M Plotter databases. Their major target genes (BNIP3, RRM2, and GOT1) were closely related to the stage, grade, and survival outcomes of ccRCC by the validation of multiple databases. Additionally, we found two groups had a significant distinct pattern of immune function, immune checkpoint, and immune infiltration, which may lead to different survival benefits. Conclusions: The FRlncRNA signature was accurate and act as reliable tools for predicting clinical outcomes and the immune microenvironment of patients with ccRCC, which may be molecular biomarkers and therapeutic targets.

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Abstract: Protein tyrosine kinases (PTKs) are a class of proteins with tyrosine kinase activity that phosphorylate tyrosine residues of critical molecules in signaling pathways. Their basal function is essential for maintaining normal cell growth and differentiation. However, aberrant activation of PTKs caused by various factors can deviate cell function from the expected trajectory to an abnormal growth state, leading to carcinogenesis. Inhibiting the aberrant PTK function could inhibit tumor growth. Therefore, tyrosine kinase inhibitors (TKIs), target-specific inhibitors of PTKs, have been used in treating malignant tumors and play a significant role in targeted therapy of cancer. Currently, drug resistance is the main reason for limiting TKIs efficacy of cancer. The increasing studies indicated that tumor microenvironment, cell death resistance, tumor metabolism, epigenetic modification and abnormal metabolism of TKIs were deeply involved in tumor development and TKI resistance, besides the abnormal activation of PTK-related signaling pathways involved in gene mutations. Accordingly, it is of great significance to study the underlying mechanisms of TKIs resistance and find solutions to reverse TKIs resistance for improving TKIs efficacy of cancer. Herein, we reviewed the drug resistance mechanisms of TKIs and the potential approaches to overcome TKI resistance, aiming to provide a theoretical basis for improving the efficacy of TKIs.

Genomic Risk Factors for Cervical Cancer

Abstract: Cervical cancer is the fourth common cancer amongst women worldwide. Infection by high-risk human papilloma virus is necessary in most cases, but not sufficient to develop invasive cervical cancer. Despite a predicted genetic heritability in the range of other gynaecological cancers, only few genomic susceptibility loci have been identified thus far. Various case-control association studies have found corroborative evidence for several independent risk variants at the 6p21.3 locus (HLA), while many reports of associations with variants outside the HLA region remain to be validated in other cohorts. Here, we review cervical cancer susceptibility variants arising from recent genome-wide association studies and meta-analysis in large cohorts and propose 2q14 (PAX8), 17q12 (GSDMB), and 5p15.33 (CLPTM1L) as consistently replicated non-HLA cervical cancer susceptibility loci. We further discuss the available evidence for these loci, knowledge gaps, future perspectives, and the potential impact of these findings on precision medicine strategies to combat cervical cancer.