Guanghui Cheng

TGM2 Regulates Radiosensitivity via POGZ ‐Mediated Repair of DNA Double‐Strand Breaks in Cervical Cancer

ABSTRACT The high capacity of cancer cells for DNA damage repair constitutes a critical factor contributing to their radioresistance. Previous studies have demonstrated that aberrant expression of transglutaminase 2 (TGM2) is linked to treatment resistance. However, the role of TGM2 in cervical cancer radiosensitivity and its underlying mechanisms remain unclear. In this study, we found that TGM2 was significantly upregulated in radioresistant cervical cancer cells and tissues. TGM2 knockdown significantly enhanced the radiosensitivity of cervical cancer cells, while TGM2 overexpression conferred radioresistance. TGM2 depletion exacerbated ionizing radiation (IR)‐induced DNA double‐strand breaks (DSBs). Mechanistically, IR triggered the nuclear translocation of TGM2, where it physically interacted with POGO transposable element derived with ZNF domain protein (POGZ) and upregulated POGZ protein levels. TGM2 knockdown impaired BRCA1 recruitment to DSB sites, phenocopying POGZ depletion effects. Rescue experiments demonstrated that POGZ knockdown reversed the radioresistance and reduction in DNA DSBs caused by TGM2 overexpression. Subcutaneous xenograft mouse models further verified these findings and the regulatory role of TGM2 in cervical cancer radiosensitivity in vivo. Together, our results demonstrated that TGM2 regulates radiosensitivity by POGZ‐mediated DNA DSBs repair, providing a novel strategy for increasing cervical cancer radiosensitivity.

A Multi-Institutional Retrospective Analysis of Oncologic Outcomes for Patients With Locally Advanced Cervical Cancer Undergoing Platinum-Based Adjuvant Chemotherapy After Concurrent Chemoradiotherapy

Objective: To evaluated the oncologic outcomes associated with platinum-based adjuvant chemotherapy following concurrent chemoradiotherapy (CCRT) in the management of patients with locally advanced cervical cancer (LACC). Methods: A total of 695 patients with FIGO stage IB2, IIA2, IIB-IVA LACC treated at 6 medical facilities were enrolled and divided into 2 groups: 478 were assigned to CCRT alone (CCRT group) and 217 to adjuvant chemotherapy after CCRT (CCRT-ACT group). The treatment outcomes were retrospectively compared and reported after the propensity score matching (PSM) analysis. Results: With a median follow-up of 56.4 months, no statistically significant differences were found in overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and distance metastasis-free survival (DMFS) between 2 groups. In CCRT-ACT group, patients with lymph nodes involvement or squamous cell carcinoma (SCC) had significantly longer DMFS, but no significant benefit in survival outcomes were observed with more than 2 cycles of adjuvant chemotherapy. Moreover, patients with a high level of CA125 (>20.5U/mL) or SCC-Ag (>22.8μg/L) had a relatively better DFS or PFS, and grade 3-4 acute hematological toxicity, late urinary and lower gastrointestinal complications and diarrhea symptom were more frequent in CCRT-ACT group. Conclusions: Adjuvant chemotherapy after CCRT has a potential role in further improving disease control for LACC patients with lymph nodal-metastasis or SCC with a high level of CA125 or SCC-Ag. Due to increased treatment-related complications and diarrhea symptom affecting the quality of life, post-CCRT adjuvant chemotherapy with excessive cycles was not be considered as the most appropriate choice in general.