Huan Dou

CD81 Aggravates Ovarian Cancer Progression via p‐Cresyl Sulfate‐Mediated Mitophagy in Tim4+ Tumour‐Associated Macrophages

ABSTRACTOvarian cancer (OC) is characterised by widespread peritoneal metastasis. Tetraspanin CD81 is predominantly located at the cellular membrane and exhibits inconsistent roles in tumour progression. However, its precise function in OC remains unclear. We found that CD81 expression was significantly elevated in tumour tissues from OC patients with poor prognosis, and it directly promoted proliferation, and migration of OC cells. Stable knock‐down of CD81 expression ameliorated disease progression in a murine model of OC and induced metabolic responses in OC cells. Metabolomics and mass spectrometry identified the protein‐bound toxin p‐cresyl sulfate (PCS) as a key metabolite regulated by the CD81‐FAK signalling axis. One aspect is that PCS promoted the growth of OC cells. Furthermore, tumour‐derived PCS combined with Cdh1 to enhance Bnip3‐dependent mitophagy activity of Tim4 positive tumour‐associated macrophages (TAMs). Intraperitoneal injection of PCS reversed the therapeutic effects observed following CD81 knock‐down; the mitophagy of reprogrammed Tim4+ TAMs was also promoted, accompanied by alterations in antitumor immunity. In summary, we elucidated CD81 prompted Tim4+ TAMs mitophagy to induce OC progression via FAK/PCS/Cdh1 pathway, deepen our understanding of OC pathogenesis.

FoxO1 promotes ovarian cancer by increasing transcription and METTL14‐mediated m6A modification of SMC4

AbstractThe transcription factor forkhead box protein O1 (FoxO1) is closely related to the occurrence and development of ovarian cancer (OC), however its role and molecular mechanisms remain unclear. Herein, we found that FoxO1 was highly expressed in clinical samples of OC patients and was significantly correlated with poor prognosis. FoxO1 knockdown inhibited the proliferation of OC cells in vitro and in vivo. ChIP‐seq combined with GEPIA2 and Kaplan–Meier database analysis showed that structural maintenance of chromosome 4 (SMC4) is a downstream target of FoxO1, and FoxO1 promotes SMC4 transcription by binding to its −1400/−1390 bp promoter. The high expression of SMC4 significantly blocked the tumor inhibition effect of FoxO1 knockdown. Furtherly, FoxO1 increased SMC4 mRNA abundance by transcriptionally activating methyltransferase‐like 14 (METTL14) and increasing SMC4 m6A methylation on its coding sequence region. The Cancer Genome Atlas dataset analysis confirmed a significant positive correlation between FoxO1, SMC4, and METTL14 expression in OC. In summary, this study revealed the molecular mechanisms of FoxO1 regulating SMC4 and established a clinical link between the expression of FoxO1/METTL14/SMC4 in the occurrence of OC, thus providing a potential diagnostic target and therapeutic strategy.