Hui Zhang

A Membrane-Retained DNA Aptamer Promotes Intracellular Platinum Accumulation and Chemosensitization in Ovarian Cancer

Cisplatin resistance remains a major obstacle in the effective treatment of ovarian cancer. Here, we report a membrane-retained DNA aptamer, DR-A2, discovered via Cell-SELEX using cisplatin-resistant ovarian cancer cells as the selection target. DR-A2 exhibited high affinity and specificity toward drug-resistant ovarian cancer cells and their secreted exosomes, while showing negligible binding to drug-sensitive parental cells or normal epithelial cells. Mechanistic studies revealed that DR-A2 increases intracellular cisplatin retention in resistant cells. In vivo, DR-A2 preferentially accumulated in cisplatin-resistant xenografts and significantly boosted the antitumor efficacy of cisplatin without causing systemic toxicity. These results validate DR-A2 as a bifunctional aptamer capable of both selective tumor recognition and chemosensitization, offering a promising strategy to overcome platinum resistance in ovarian cancer.

FBXO7, a tumor suppressor in endometrial carcinoma, suppresses INF2-associated mitochondrial division

AbstractEndometrial carcinoma (ECa) is the most common malignant gynecological cancer, with an increased incidence and fatality rate worldwide, while the pathogenesis is still largely unknown. In this study, we confirmed that FBXO7, a gene coding FBXO7 E3 ubiquitin ligase, is significantly downregulated and mutated (5.87%; 31/528) in ECa specimens, and the abnormal low expression and mutations of FBXO7 are associated with the occurrence of ECa. We also identify the excessive expression of INF2 protein, a key factor that triggers mitochondrial division by recruiting the DRP1 protein, and the elevated INF2 protein is significantly negatively correlated with the low FBXO7 protein in ECa specimens. Mechanistically, FBXO7 restrains ECa through inhibiting INF2-associated mitochondrial division via FBXO7-mediated ubiquitination and degradation of INF2. Moreover, we found that ECa-associated FBXO7 mutants are defective in the ubiquitination and degradation of INF2, promoting ECa cells proliferation, migration and apoptosis inhibition via inducing mitochondrial hyper-division. In addition, we found that it could reverse FBXO7 deletion or ECa-associated FBXO7 mutants-induced proliferation, migration, apoptosis inhibition and mitochondrial hyper-division of ECa cells by INF2 or DNM1L knockdown, or DRP1 inhibitor Mdivi-1. In summary, our study shows that FBXO7 acts as a novel tumor suppressor in ECa by inhibiting INF2-DRP1 axis-associated mitochondrial division through the ubiquitination and degradation of INF2 while the effect is destroyed by ECa-associated FBXO7 and INF2 mutants, highlights the key role of FBXO7-INF2-DRP1 axis in ECa tumorigenesis and provides a new viewpoint to treat ECa patients with FBXO7 deletion or mutations by targeting INF2-DRP1 axis-associated mitochondrial division.

Deregulation of SPOP in Cancer

Abstract Speckle-type POZ protein (SPOP) is a substrate-binding adaptor of the CULLIN3/RING-box1 E3 ubiquitin ligase complex. SPOP is frequently mutated in prostate and endometrial cancers, whereas it is overexpressed in renal cell carcinoma (RCC). SPOP can mediate both degradable and nondegradable polyubiquitination of a number of substrates with diverse biological functions such as androgen receptor (AR), SRC-3, TRIM24, BRD4, PD-L1, 53BP1, GLP/G9a, c-Myc, SENP7, among others. Cancer-associated SPOP mutants often impair SPOP binding and polyubiquitination of its substrates to influence various cancer-relevant pathways, which include androgen/AR signaling, DNA repair and methylation, cellular stress surveillance, cancer metabolism, and immunity. Although SPOP is recognized as a tumor suppressor in prostate and endometrial cancers, it acts like an oncoprotein in RCC. This review provides an overview of the recent progress in understanding of the upstream regulators of SPOP and its downstream targets, highlights the significant impact of SPOP mutations and overexpression on cancer pathogenesis, and discusses the potential of targeting SPOP for cancer treatment.

Intestinal perforation in recurrent cervical cancer following bevacizumab and pembrolizumab therapy: A case report

Rationale: Since the advent of immunotherapy in clinical practice, it has profoundly transformed the paradigm of cancer treatment and has been rapidly adopted in clinical settings. Concurrently, the combination of immunotherapy with anti-angiogenic therapy has shown great promise in clinical research. The inevitable joint application brings about a greater number of adverse reactions. These adverse reactions are often perplexing, with the uncertainty of whether they stem from immunotherapy, anti-angiogenic therapy, or both. This is a case report of adverse reactions occurring when immune drugs and anti-vascular drugs are used together. This case is analyzed to provide a warning for adverse reactions in the clinical application of anti-angiogenic therapy combined with immunotherapy. Patient concerns: A 52-year-old cervical cancer patient with metastases had abdominal pain and fever post-treatment with bevacizumab, pembrolizumab, and chemotherapy, suggesting intestinal perforation. Diagnoses: After 2 chemotherapy cycles with bevacizumab and pembrolizumab, the patient had fever up to 39°C and abdominal pain. Exam showed tenderness, rigidity, and weak bowel sounds. Blood tests revealed leukocytosis and neutrophilia. Imaging indicated pneumoperitoneum and possible intestinal obstruction. Interventions: Emergency laparotomy revealed a small intestine perforation with strictures, leading to resection and ileostomy due to edema. Outcomes: The postoperative recovery was good. We consider intestinal perforation caused by bevacizumab. Therefore, the patient was subsequently discontinued from bevacizumab and continued to receive paclitaxel, cisplatin and pembrolizumab. At present, the patient has finished chemotherapy and is receiving pembrolizumab maintenance therapy with no significant gastrointestinal adverse reactions. Lessons: Anti-angiogenic drugs and immunotherapy drugs each have their own side effects, and the occurrence of adverse reactions becomes more complex when used in combination. In the clinical process of combined medication, more attention should be paid to adverse reactions, early identification of severe adverse reactions, and active management.

Glycoproteomics-based signatures for tumor subtyping and clinical outcome prediction of high-grade serous ovarian cancer

Abstract Inter-tumor heterogeneity is a result of genomic, transcriptional, translational, and post-translational molecular features. To investigate the roles of protein glycosylation in the heterogeneity of high-grade serous ovarian carcinoma (HGSC), we perform mass spectrometry-based glycoproteomic characterization of 119 TCGA HGSC tissues. Cluster analysis of intact glycoproteomic profiles delineates 3 major tumor clusters and 5 groups of intact glycopeptides. It also shows a strong relationship between N-glycan structures and tumor molecular subtypes, one example of which being the association of fucosylation with mesenchymal subtype. Further survival analysis reveals that intact glycopeptide signatures of mesenchymal subtype are associated with a poor clinical outcome of HGSC. In addition, we study the expression of mRNAs, proteins, glycosites, and intact glycopeptides, as well as the expression levels of glycosylation enzymes involved in glycoprotein biosynthesis pathways in each tumor. The results show that glycoprotein levels are mainly controlled by the expression of their individual proteins, and, furthermore, that the glycoprotein-modifying glycans correspond to the protein levels of glycosylation enzymes. The variation in glycan types further shows coordination to the tumor heterogeneity. Deeper understanding of the glycosylation process and glycosylation production in different subtypes of HGSC may provide important clues for precision medicine and tumor-targeted therapy.

The role of S-nitrosylation of PFKM in regulation of glycolysis in ovarian cancer cells

AbstractOne of the malignant transformation hallmarks is metabolism reprogramming, which plays a critical role in the biosynthetic needs of unchecked proliferation, abrogating cell death programs, and immunologic escape. However, the mechanism of the metabolic switch is not fully understood. Here, we found that the S-nitrosoproteomic profile of endogenous nitrogen oxide in ovarian cancer cells targeted multiple components in metabolism processes. Phosphofructokinase (PFKM), one of the most important regulatory enzymes of glycolysis, was S-nitrosylated by nitric oxide synthase NOS1 at Cys351. S-nitrosylation at Cys351 stabilized the tetramer of PFKM, leading to resist negative feedback of downstream metabolic intermediates. The PFKM-C351S mutation decreased the proliferation rate of cultured cancer cells, and reduced tumor growth and metastasis in the mouse xenograft model. These findings indicated that S-nitrosylation at Cys351 of PFKM by NOS1 contributes to the metabolic reprogramming of ovarian cancer cells, highlighting a critical role of endogenous nitrogen oxide on metabolism regulations in tumor progression.