Hui Chen

Advances in Targeting HER2 across Cancer Subtypes: A Pan-Tumor Approach

Abstract Human epidermal growth factor receptor 2 (HER2) is an established therapeutic target in multiple solid tumors, particularly breast and gastric cancers. Significant advancements have been made in the development of HER2-targeted therapies, including monoclonal antibodies, tyrosine kinase inhibitors, antibody–drug conjugates (ADC), and novel bispecific antibodies. These agents have revolutionized the treatment landscape for HER2-positive metastatic cancers, resulting in improved progression-free and overall survival, and quality of life for patients. Beyond breast and gastric cancers, HER2 expression/amplification has been observed in other solid tumors, such as colorectal, lung, bladder, ovarian, and biliary tract cancers, offering new opportunities for personalized therapy in a larger patient population. In this review, we highlight the current state of HER2-targeted treatment strategies across HER2-expressing solid tumors, discussing the clinical efficacy, adverse event profiles, and challenges of existing therapies. We explore emerging treatment approaches, including novel agents such as HER2-targeting ADCs, combination therapies, and strategies to overcome resistance mechanisms. Additionally, we examine the role of HER2 expression heterogeneity, biomarker-driven patient selection, and diagnostic tools for patient selection and optimization of treatment outcomes. This review also investigates ongoing challenges in expanding HER2-targeted therapies, including addressing intrinsic and acquired resistance and tailoring strategies to low HER2-expressing or HER2-mutant tumors. Lastly, we provide insights into future directions, emphasizing the importance of precision oncology to broaden the therapeutic opportunities of HER2-targeted therapies across diverse HER2-driven malignancies.

The Downregulation of MMP23B Facilitates the Suppression of Vitality and Induction of Apoptosis in Endometrial Cancer Cells

AbstractEndometrial cancer is a malignant tumor that commonly occurs in the female reproductive system and its incidence is still increasing. The mechanism of the development of endometrial cancer has not yet been fully clarified, so we need to continuously study the relevant mechanisms of endometrial cancer and continue to explore its biomarkers in order to discover more precise and effective treatment methods for endometrial cancer. RT-qPCR (Real-Time quantitative Polymerase Chain Reaction) experiments were used to detect the expression level of MMP23B (Matrix Metalloproteinase 23B) in endometrial cancer cells; the clinical data of the TCGA (The Cancer Genome Atlas) database were downloaded, and gene expression profiles were analyzed to investigate the correlation between MMP23B (Matrix Metalloproteinase 23B) and the survival prognosis of endometrial cancer, and functional enrichment analysis was performed on MMP23B (Matrix Metalloproteinase 23B) related genes. After silencing MMP23B (Matrix Metalloproteinase 23B), CCK8 (Cell Counting Kit-8), RT-qPCR (Real-Time quantitative Polymerase Chain Reaction), scratch assay, and transwell assay were used to detect cell viability, levels of apoptotic factors, migration rate, and invasion number of endometrial cancer, respectively. MMP23B (Matrix Metalloproteinase 23B) was highly expressed in endometrial cancer, which is closely related to a poor survival prognosis for endometrial cancer, and may act on endometrial cancer through apoptosis-related functions. The downregulation of MMP23B (Matrix Metalloproteinase 23B) reduced the cell viability of endometrial cancer cells, upregulated the expression levels of CASP3 (Caspase-3), CASP8 (Caspase-8) and CASP9 (Caspase-9) in cells, and inhibited cell migration and invasion.

NF-κB Activation Is Essential for Cervical Cell Proliferation and Malignant Transformation

NF-κB, a multifunctional transcription factor, is linked to cancer initiation and progression. As a key immune mediator, it may play a crucial role in HPV-induced cervical carcinogenesis. However, consensus is lacking on the activation timing of NF-κB during the transition from cervical intraepithelial neoplasia (CIN) to cervical squamous cell carcinoma (CSCC). In this study, immunohistochemical analysis was performed to examine RELA, one of the important members of the NF-κB family, and phospho-RELA expression in different cervical lesions. Then, we analyzed NF-κB regulation of differentially expressed genes (DEGs) in cervical lesions vs. normal tissues. Gene enrichment identified oncogenic DEGs, followed by expression and survival analyses. The impact of NF-κB activation on cervical cell proliferation, migration, and oncogenic regulation, as well as the effects of inhibiting NF-κB, were examined. Our study showed that NF-κB activation starts in cervical simple hyperplasia and intensifies as CIN evolves to CSCC. NF-κB-regulated DEGs show stage-specific functions: immune regulation in CIN and cancer promotion in CSCC. Short-term NF-κB activation boosts cervical cell proliferation and migration, which is reversible by an NF-κB inhibitor. Long-term NF-κB activation promotes the expression of cancer-promoting genes in normal cells and also maintains them in cancer tissues, which is linked to poorer prognosis. Inhibiting NF-κB downregulates these genes in cancer cells and suppresses the oncogenic abilities of cervical cancer cells. Collectively, NF-κB activation initiates during the simple hyperplasia stage of cervical cells, stimulating proliferation, migration, and oncogene expression. Throughout the transition from CIN to CSCC, NF-κB activation progressively intensifies, and its long-term activation promotes carcinogenesis. Thus, NF-κB is crucial in mediating cervical oncogenic transformation.

Knowledge of HPV, its vaccines, and attitudes toward HPV vaccines among obstetrician-gynecologists, pediatricians and immunization services providers in Western China

In mainland China, HPV vaccines have been available to the public. However, only a few related studies among health care providers, as the key information providers, were reported although public concerns on HPV vaccines still exist. In this study, we aim to assess the knowledge of HPV, its vaccines, and attitudes toward HPV vaccines among the three most important groups of health care providers in Western China. This was a cross-sectional questionnaire-based study. Health care providers including obstetrician-gynecologists (OB-GYNs), pediatricians, and immunization service providers in Western China were investigated regarding their knowledge of HPV and its vaccines and their attitudes toward HPV vaccines. Of 1079 health care providers completing the survey, 1015 (94.1%) knew HPV infection is the primary cause of cervical cancer. However, lower knowledge levels of other HPV-related diseases were also found (43.2%). About three-quarters (74.1%) of practitioners interviewed would be willing to recommend HPV vaccination, which was found to be lower among the OB-GYNs (69.6%) and the pediatricians (73.2%). "Lack of relevant knowledge," "concerns on safety and efficacy" and price were the three most important concerns surrounding HPV vaccination. The interviewed practitioners did not have adequate knowledge of HPV and its vaccines in depth. Education interventions are highly recommended to the health care providers, especially for OB-GYNs and pediatricians, to increase the coverage of HPV vaccination among the population. For the currently high price of vaccines, a future co-sharing mechanism between the government, the providers, and the individuals might be a solution.

Effect of an educational intervention on human papillomavirus (HPV) knowledge and attitudes towards HPV vaccines among healthcare workers (HCWs) in Western China

Healthcare workers (HCWs) play a key role in the recommendation of HPV vaccination. Our study aimed to understand to what extent a structured health intervention could change the knowledge and attitudes toward HPV and its vaccines among HCWs in Western China. This was a multi-center, questionnaire-based interventional study conducted across 12 cities of seven provinces in Western China, from November 2018 to July 2019. Participants were recruited from local health systems by e-invitation. Questionnaires were administered to participants before and after the intervention. A total of 1448 HCWs attended the educational lectures and 1354 participants completed both pre- and post-study questionnaires. In general, HCWs had satisfactory baseline knowledge regarding HPV and its vaccines compared with other populations, and a significantly higher knowledge level was observed after the intervention. However, some more specific knowledge on the vaccination procedures, other HPV-related diseases and whether HPV testing was required before vaccination was relatively poor. Following the educational intervention, the correct responses to the above questions increased ( Educational intervention on HPV and its vaccines is effective in improving HCWs' knowledge levels and willingness to recommend HPV vaccines. Future educational interventions should focus more on knowledge regarding HPV-related diseases and HPV vaccination. Education campaigns targeting rural HCWs are urgently needed in the near future.

PAX2 is regulated by estrogen/progesterone through promoter methylation in endometrioid adenocarcinoma and has an important role in carcinogenesis via the AKT / mTOR signaling pathway

Abstract Endometrioid adenocarcinoma (EEC) is one of the most common cancers of the female reproductive system. In recent years, much emphasis has been placed on early diagnosis and treatment. PAX2 (Paired box 2) inactivation is reportedly an important biomarker for endometrioid intraepithelial neoplasia (EIN) and EEC. However, the role of PAX2 in EEC carcinogenesis remains unclear. PAX2 expression and associated clinical characteristics were analyzed via The Cancer Genome Atlas, Gene Expression Omnibus, and Cancer Cell Line Encyclopedia databases and clinical paired EIN/EEC tissue samples. Bioinformatic analysis was conducted to identify the putative molecular function and mechanism of PAX2. Cell proliferation, colony formation, cell migration, and invasion assays in vitro , and mouse xenograft models were utilized to study the biological functions of PAX2 in vivo . Pyrosequencing and the demethylating drug 5‐Aza‐dc were used to verify promoter methylation in clinical tissues and cell lines, respectively. The mechanism underlying the regulatory effect of estrogen (E2) and progesterone (P4) on PAX2 expression was investigated by receptor block assay and double luciferase reporter assay. PAX2 expression was found to be significantly downregulated in EIN and EEC tissues, its overexpression inhibited EEC cell malignant behaviors in vivo and in vitro and inhibited the AKT/mTOR signaling pathway. PAX2 inactivation in EEC was related to promoter methylation, and its expression was regulated by E2 and P4 through their receptors via promoter methylation. Our findings elucidated the expression and function of PAX2 in EEC and have provided hitherto undocumented evidence of the underlying molecular mechanisms. PAX2 expression is suppressed by estrogen prompting its methylation through estrogen receptor. Furthermore, PAX2 regulates the AKT/mTOR signaling pathway to influence EEC progression. © 2024 The Pathological Society of Great Britain and Ireland.