Xing Xie

Molecular profile-based recommendations for postoperative adjuvant therapy in early endometrial cancer with high-intermediate or intermediate risk: a Chinese randomized phase III trial (PROBEAT)

The use of molecular categorisation is shifting paradigm towards the use of molecular information to refine risk stratification in endometrial cancer (EC). To date, evidence to support molecular-guided therapies is limited to retrospective studies and secondary molecular analyses of patients receiving standard treatment. The PROBEAT study is the first randomized phase III trial to evaluate tailored adjuvant treatment based on WHO-endorsed molecular classification in Chinese EC patients. It is expected to provide a clinical decision-making tool for adjuvant treatment of patients with high-intermediate risk (HIR) or intermediate risk (IR) EC to better optimise and personalise patient care and increase relapse-free survival. The PROBEAT trial is a prospective, multicentre study led by Women's Hospital of Zhejiang University Gynaecologic Oncology Group. Recruitment started on January 24, 2022, and 590 patients with HIR or IR endometrioid EC are expected to be recruited from 13 clinical centres in China. All tumor tissues will be classified into four molecular subtypes ( ClinicalTrials.gov Identifier: NCT05179447.

SURF4 maintains stem-like properties via BIRC3 in ovarian cancer cells

As cancer stem cells (CSCs) are considered as the origin of tumor development, recurrence, and drug resistance, we aimed to explore the mechanism related to modulating stemness in CSCs, thus facilitating to search for new therapeutic strategy for ovarian cancer. In this study, ovarian cancer stem cells (OCSCs) induced from cell line 3AO and A2780 were enriched in serum-free medium (SFM). The effect of SURF4 on CSC-like properties was evaluated by sphere-forming assays, re-differentiation assays, quantitative real-time polymerase chain reaction, flow cytometry, Western blotting, cell viability assays and in vivo xenograft experiments. The downstream molecule participating in SURF4 maintaining stemness was screened by RNA-sequencing and identified by the experiments of gene function. SURF4 was upregulated expressed in OCSCs. Knockdown of SURF4 reduced the expression of the related stem markers (SOX2 and c-MYC), inhibited self-renewal ability, and improved the sensitivity to chemotherapeutic drugs (paclitaxel and cisplatin) in OCSCs. SURF4 knockdown also inhibited tumorigenesis in nonobese diabetic/severe combined immunodeficiency mice. BIRC3 expression was controlled by SURF4, and BIRC3 showed the similar effect as SURF4 did, and BIRC3 overexpression partially recovered stem-like properties abolished by SURF4 knockdown. Our findings suggest that SURF4 possesses the ability to maintain stemness of OCSCs via BIRC3, and may serve as a potential target in stem cell-targeted therapy for ovarian cancer.

Potential of peptide‐engineered exosomes with overexpressed miR‐92b‐3p in anti‐angiogenic therapy of ovarian cancer

AbstractIntroductionExosomal microRNA (miRNA) as a mediator of intercellular communication plays an essential part in tumor‐relevant angiogenesis. Therapy against angiogenesis has been demonstrated to have a remarkable antitumor efficacy in various malignancies, but not as expected in ovarian cancer.MethodsExosomes were isolated by ultracentrifugation. Exosomal miRNA sequencing and gene function experiments were used to identify the differential expressed miRNAs in exosomes and their mRNA targets. SKOV3 cell line that stably overexpressed miR‐92b‐3p was constructed by lentivirus. In vitro, angiogenesis was analyzed by tube formation assay and migration assay. The angiogenic and antitumor effects in vivo were assessed in zebrafish and nude mouse models. Combination index was calculated to assess the synergetic inhibition of angiogenesis between miR‐92b‐3p and Apatinib. Peptides were conjugated with exosomal membranes to obtain engineered exosomes.ResultsOvarian cancer cell‐derived exosomes facilitated the angiogenesis and migration capability of vascular endothelial cells in vitro and in vivo. The expression of miR‐92b‐3p was much lower in ovarian cancer cell‐derived exosomes than that in immortalized ovarian epithelial cell‐derived exosomes. The exosomal miR‐92b‐3p modulated tumor‐associated angiogenesis via targeting SOX4. Besides, Peptide‐engineered exosomes with overexpressed miR‐92b‐3p showed the stronger abilities of anti‐angiogenesis and antitumor than parental exosomes, whether alone or combined with Apatinib.ConclusionsOur findings demonstrate the effect and mechanism of exosomal miR‐92b‐3p from ovarian cancer cells on tumor‐associated angiogenesis and the potential of artificially generated exosomes with overexpressed miR‐92b‐3p to be used as anti‐angiogenic agent, which may provide a new approach for anti‐angiogenic therapy of ovarian cancer.

LncRNA SPOCD1-AS from ovarian cancer extracellular vesicles remodels mesothelial cells to promote peritoneal metastasis via interacting with G3BP1

AbstractBackgroundMetastasis is the key cause of death in ovarian cancer patients. To figure out the biological nature of cancer metastasis is essential for developing effective targeted therapy. Here we investigate how long non-coding RNA (lncRNA) SPOCD1-AS from ovarian cancer extracellular vesicles (EVs) remodel mesothelial cells through a mesothelial-to-mesenchymal transition (MMT) manner and facilitate peritoneal metastasis.MethodsEVs purified from ovarian cancer cells and ascites of patients were applied to mesothelial cells. The MMT process of mesothelial cells was assessed by morphology observation, western blot analysis, migration assay and adhesion assay. Altered lncRNAs of EV-treated mesothelial cells were screened by RNA sequencing and identified by qRT-PCR. SPOCD1-AS was overexpressed or silenced by overexpression lentivirus or shRNA, respectively. RNA pull-down and RNA immunoprecipitation assays were conducted to reveal the mechanism by which SPOCD1-AS remodeled mesothelial cells. Interfering peptides were synthesized and applied. Ovarian cancer orthotopic implantation mouse model was established in vivo.ResultsWe found that ovarian cancer-secreted EVs could be taken into recipient mesothelial cells, induce the MMT phenotype and enhance cancer cell adhesion to mesothelial cells. Furthermore, SPOCD1-AS embedded in ovarian cancer-secreted EVs was transmitted to mesothelial cells to induce the MMT process and facilitate peritoneal colonization in vitro and in vivo. SPOCD1-AS induced the MMT process of mesothelial cells via interacting with G3BP1 protein. Additionally, G3BP1 interfering peptide based on the F380/F382 residues was able to block SPOCD1-AS/G3BP1 interaction, inhibit the MMT phenotype of mesothelial cells, and diminish peritoneal metastasis in vivo.ConclusionsOur findings elucidate the mechanism associated with EVs and their cargos in ovarian cancer peritoneal metastasis and may provide a potential approach for metastatic ovarian cancer therapeutics.

PROfiling Based Endometrial Cancer Adjuvant Therapy

This is a prospective, multicenter, randomized phase III trial among women with endometrioid adenocarcinoma with high-intermediate and intermediate risk features to investigate the role of integrated genomic-pathologic classification to determine if participants should receive no adjuvant therapy, vaginal brachytherapy, external beam radiotherapy or chemo-radiation therapy based on molecular features as compared to standard radiation therapy.