Ming Sun

KPNA5 Suppresses Malignant Progression of Ovarian Cancer Through Importing the PTPN4 Into the Nucleus

ABSTRACTBackgroundAbnormal protein localization due to disrupted nucleoplasmic transport is common in tumor cells, but its mechanisms are not well understood. Nuclear pore complexes and nuclear transporter proteins are crucial for protein transport between the nucleus and cytoplasm. Evidence increasingly shows that abnormal expression of karyopherin family proteins disrupts protein translocation, affecting processes like cell differentiation, proliferation, apoptosis, and transcriptional regulation. However, their functions and roles in ovarian cancer remain unclear.MethodsThe expression level of KPNA5 in ovarian cancer tissues and cells was detected by IHC, Western blot, and qPCR. CCK‐8 and colony formation assays were used to assess cell proliferation ability. Transwell assay was conducted to determine cell migration and invasion capacity. A xenograft model was used to assess the effect of KPNA5 on tumor growth in vivo.ResultsKPNA5 expression is downregulated in ovarian cancer (OC) tissues. Low KPNA5 levels were associated with poor survival in OC patients, validated by an OC tissue sample cohort. Overexpression of KPNA5 significantly suppressed OC cell proliferation, tumor growth, and invasion in both in vitro and in vivo studies. Mechanistically, KPNA5 recognizes nuclear localization signals (NLSs) in PTPN4, mediating its nuclear transport and inhibiting STAT3 phosphorylation and its downstream signaling pathway. Similarly, PTPN4 overexpression reduced OC cell viability and invasion, also suppressing STAT3 phosphorylation.ConclusionsOur findings identify KPNA5 as a tumor suppressor in OC, presenting a potential therapeutic target for OC treatment.

A novel TREM1/DAP12-based multiple chain CAR-T cell targets PTK7 in ovarian cancer therapy

While CAR-T cell therapy has shown success against hematological tumors, its effectiveness for solid tumors, including ovarian cancer, remains unsatisfactory. This study aimed to develop and evaluate the efficacy of novel chimeric antigen receptor T (CAR-T) cells targeting PTK7 through TREM1/DAP12 signaling against ovarian cancer. The expression of PTK7 in ovarian cancer tissues and cells was evaluated using immunohistochemical staining and flow cytometric analysis. The anti-tumor effects of PTK7 CAR-T cells were assessed in vitro using real-time cell analysis and enzyme-linked immunosorbent assay, and in vivo using a xenograft tumor model. PTK7 was significantly expressed in ovarian cancer tissues and cells. PTK7-targeting CAR-T cells based on TREM1/DAP12 signaling exhibited potent cytotoxicity against ovarian cancer cells expressing PTK7 in vitro, and effectively eradicated tumors in vivo. Our findings suggest that TREM1/DAP12-based PTK7 CAR-T cells have potential as a treatment strategy for ovarian cancer. Further studies are needed to evaluate the safety and efficacy of this approach in clinical trials.

A therapeutic multi-epitope protein vaccine targeting HPV16 E6 E7 elicits potent tumor regression and cytotoxic immune responses

Objective: Cervical cancer caused by persistent high-risk human papillomavirus (hrHPV) infection remains a leading cause of cancer-related mortality in women. As prophylactic HPV vaccines cannot eliminate existing infections, developing therapeutic vaccines targeting HPV E6/E7 oncoproteins is critical for reversing precancerous lesions. This study aimed to design a novel multi-epitope vaccine against HPV16, incorporating newly identified immunodominant epitopes and evaluating the therapeutic efficacy. Methods: The multi-epitope vaccine HSP70-12P was bioinformatically designed to include cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) epitopes from HPV16 E6/E7, which were fused to the C-terminal domain (residues 359–610) of Mycobacterium tuberculosis HSP70 as an adjuvant. Two formulations were used, as follows: (1) protein-based Pro-HSP70-12P; and (2) DNA-based DNA-HSP70-12P. Therapeutic efficacy was evaluated in TC-1 tumor-bearing mouse models. Tumor regression, survival rates, and immune correlates (T cell responses and cytokine profiles) were assessed. Immunodominant epitopes were identified using ELISpot. Results: The Pro-HSP70-12P protein vaccine induced strong immune responses and provided lasting antitumor protection. The vaccine activated cell-mediated immunity and stimulated effector memory T cells in the HPV-16-related tumor mouse model, resulting in strong tumor clearance effects. Pro-HSP70-12P demonstrated superior performance compared to the DNA-HSP70-12P vaccine, achieving complete regression of small tumors (diameter < 2 mm) with a single dose and conferring long-lasting protection in TC-1 rechallenge experiments. Three novel immunodominant epitopes were identified (E6-38-45, E6-124-132, and E7-50-57). The E6 epitopes address a critical gap in E6-targeted vaccine design. Conclusions: The multi-epitope protein vaccine, Pro-HSP70-12P, represents a potent therapeutic candidate against HPV-driven malignancies, which has the capacity to induce tumor regression and long-term immunity. These findings support further clinical development.