Yincheng Teng

The involvement of lncRNA EMSLR in the disulfidptosis and progression of endometrial carcinoma

The incidence of endometrial cancer (EC) continues to rise. Disulfidptosis, a novel form of cell death, may represent a potential therapeutic target in EC. Through bioinformatic analysis of The Cancer Genome Atlas (TCGA) database, E2F1 mRNA-stabilizing lncRNA (EMSLR) was identified as a lncRNA related to disulfidptosis in EC. Functional assays, including cell proliferation and xenograft assays, demonstrated that knockdown of EMSLR significantly impeded EC cell proliferation, whereas overexpression of EMSLR promoted cell viability. Additionally, EMSLR was found to be associated with glucose uptake and NADPH production in glucose-restricted culture conditions. Moreover, downregulation of EMSLR markedly increased cell death and induced cytoskeletal collapse under glucose deprivation, as evidenced by F-actin and cell death staining. Notably, we observed a strong correlation between EMSLR and the c-MYC-GLUT1 pathway. Mechanistically, EMSLR was found to mediate the expression and nuclear translocation of c-MYC, thereby regulating the progression of EC and its associated disulfidptosis. In conclusion, EMSLR is identified as a disulfidptosis-related gene in endometrial cancer. Elucidating the function and molecular mechanisms of EMSLR in EC presents a promising avenue for therapeutic intervention in patients.

Elevated expression of Golgi Transport 1B promotes the progression of cervical cancer by activating the NF-kappaB signaling pathway via interaction with TANK-Binding Kinase 1

Abstract As a preventable disease, cervical cancer (cervical squamous cell carcinoma and endocervical adenocarcinoma—CESC) remains a tumor with high morbidity and mortality worldwide, underscoring the pressing need for effective treatment strategies. This research identified Golgi transport 1B (GOLT1B) as a critical gene involved in the development of cervical cancer. Gene Expression Omnibus (GEO) datasets were investigated to determine the upregulation of GOLT1B in cervical cancer tissue compared with normal tissue. Besides, GOLT1B was found to predict poor prognosis in cervical cancer by utilizing Gene Expression Profiling Interactive Analysis (GEPIA). The functional assay indicated that GOLT1B promoted CESC viability and migration in vitro and in vivo. RNA sequencing results suggested that GOLT1B likely influenced the nuclear factor-kappaB (NF-κB) pathway. The subsequent western blot and dual luciferase reporter assay revealed the interaction between GOLT1B and TANK binding kinase 1 (TBK1), modulating the NF-κB pathway. More importantly, GOLT1B was also found to regulate immune cell infiltration, suggesting its potential role in the tumor microenvironment. In conclusion, GOLT1B promotes CESC progression via interaction with TBK1 and augmentation of NF-κB signaling-mediated cancer-associated inflammation, which provides us with a new approach to CESC target therapy.

A phase II trial of cytoreductive surgery combined with niraparib maintenance in platinum-sensitive, secondary recurrent ovarian cancer: SGOG SOC-3 study

In China, secondary cytoreductive surgery (SCR) has been widely used in ovarian cancer (OC) over the past two decades. Although Gynecologic Oncology Group-0213 trial did not show its overall survival benefit in first relapsed patients, the questions on patient selection and effect of subsequent targeting therapy are still open. The preliminary data from our pre-SOC1 phase II study showed that selected patients with second relapse who never received SCR at recurrence may still benefit from surgery. Moreover, poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance now has been a standard care for platinum sensitive relapsed OC. To our knowledge, no published or ongoing trial is trying to answer the question if patient can benefit from a potentially complete resection combined with PARPi maintenance in OC patients with secondary recurrence. SOC-3 is a multi-center, open, randomized, controlled, phase II trial of SCR followed by chemotherapy and niraparib maintenance vs chemotherapy and niraparib maintenance in patients with platinum-sensitive second relapsed OC who never received SCR at recurrence. To guarantee surgical quality, if the sites had no experience of participating in any OC-related surgical trials, the number of recurrent lesions evaluated by central-reviewed positron emission tomography-computed tomography image shouldn't be more than 3. Eligible patients are randomly assigned in a 1:1 ratio to receive either SCR followed by 6 cycles of platinum-based chemotherapy and niraparib maintenance or 6 cycles of platinum-based chemotherapy and niraparib maintenance alone. Patients who undergo at least 4 cycles of chemotherapy and must be, in the opinion of the investigator, without disease progression, will be assigned niraparib maintenance. Major inclusion criteria are secondary relapsed OC with a platinum-free interval of no less than 6 months and a possibly complete resection. Major exclusion criteria are borderline tumors and non-epithelial ovarian malignancies, received debulking surgery at recurrence and impossible to complete resection. The sample size is 96 patients. Primary endpoint is 12-month non-progression rate. ClinicalTrials.gov Identifier: NCT03983226.

Profiling and bioinformatics analyses reveal differential circular RNA expression in ovarian cancer

Ovarian cancer (OC) is the deadliest form of gynecologic malignancy, with the majority of patients being diagnosed only once the disease reaches an advanced stage owing to a lack of available biomarkers capable of accurately detecting the disease. Stable circular RNAs (circRNAs) can be found at high levels in exosomes, and there is evidence to suggest that they may be viable diagnostic biomarkers for certain cancers. However, circRNAs in the serum of OC patients have rarely been evaluated to date. We therefore sought to investigate serum circRNA profiles of OC patients, and to explore whether these sorts of circRNAs could be used to detect early OC, serving as biomarkers of disease that may allow for the earlier treatment thereof. Second-generation sequencing was used to screen differentially expressed circRNAs in OC patient serum and also in the serum obtained from healthy controls, and circRNA expression was confirmed by qPCR. A bioinformatics-based approach was then used to assess what biological functions might be affected be the altered regulation of these RNA molecules. We further conducted GO, KEGG, and network analyses to further explore the expression of circRNAs. We detected 178 differentially expressed circRNAs in OC patient serum, of which 175 were up-regulated and 3 were down-regulated. We validated 5 of these identified circRNAs by qPCR to confirm their expression, and further found these RNAs to be closely linked with FC gamma R-mediated phagocytosis, VEGF signaling, Transcriptional misregulation in cancer, Chemokine signaling, ErbB signaling, and TNF signaling based on conducted analyses. This study provides a profile of circRNAs in OC patient serum, revealing a pattern of dysregulation of these RNAs associated with OC. Our bioinformatics analysis suggested that these circRNAs are likely related to OC development, and as such they may be viable novel OC biomarkers.

Inhibiting Importin 4-mediated nuclear import of CEBPD enhances chemosensitivity by repression of PRKDC-driven DNA damage repair in cervical cancer

AbstractCervical cancer (CC) remains highest in the mortality of female reproductive system cancers, while cisplatin (CDDP) resistance is the one of main reasons for the lethality. Preceding evidence has supported that karyopherins are associated with chemoresistance. In this study, we simultaneously compared CDDP-incomplete responders with CDDP-complete responders of CC patients and CDDP‐insensitive CC cell lines with CDDP‐sensitive group. We finally identified that DNA-PKcs (PRKDC) was related to CDDP sensitivity after overlapping in CC sample tissues and CC cell lines. Further functional assay revealed that targeting PRKDC by shRNA and NU7026 (specific PRKDC inhibitor) could enhance CDDP sensitivity in vitro and in vivo, which was mediated by impairing DNA damage repair pathway in CC. Mechanistically, we found that PRKDC was transcriptionally upregulated by CCAAT/enhancer-binding protein delta (CEBPD), while intriguingly, CDDP treatment strengthened the transcriptional activity of CEBPD to PRKDC. We further disclosed that Importin 4 (IPO4) augmented the nuclear translocation of CEBPD through nuclear localization signals (NLS) to activate PRKDC-mediated DNA damage repair in response to CDDP. Moreover, we demonstrated that IPO4 and CEBPD knockdown improved CDDP-induced cytotoxicity in vitro and in vivo. Together, we shed the novel insight into the role of IPO4 in chemosensitivity and provide a clinical translational potential to enhance CC chemosensitivity since the IPO4-CEBPD-PRKDC axis is actionable via NU7026 (PRKDC inhibitor) or targeting IPO4 in combination with CDDP.

TNPO1-Mediated Nuclear Import of FUBP1 Contributes to Tumor Immune Evasion by Increasing NRP1 Expression in Cervical Cancer

Far upstream element binding protein 1 (FUBP1), a DNA-binding protein, participates in diverse tumor-promoting behaviors by regulating the expression of oncogenes in the nucleus, but the underlying mechanisms remain to be elucidated. In the present study, we found that FUBP1 mRNA and protein expressions were markedly upregulated and closely linked with poor prognosis in cervical cancer. In vitro, functional experiments showed that knockdown of FUBP1 inhibited CC cell proliferation and migration. Therefore, FUBP1 plays a prooncogenic function in CC progression. Further investigations for the first time demonstrated that nuclear localization of FUBP1 regulated the gene expression of immune checkpoint NRP1. Moreover, our work demonstrated that FUBP1 translocated into the nucleus which was mediated by interacting with Transportin-1 (TNPO1). Collectively, this study revealed that FUBP1 might be a potential therapeutic target for the restriction of tumor progression.

CDK12 Promotes Cervical Cancer Progression through Enhancing Macrophage Infiltration

Cervical cancer (CC) is a commonly diagnosed and primary consideration of cancer patient death in female reproductive system malignancy. Cyclin-dependent kinase 12 (CDK12), as a transcription-associated CDK, plays important roles in tumor-promoting behaviors, whereas the underlying mechanisms of CDK12 in CC progression are still obscure. In this report, we investigated the role of CDK12 in cervical cancer. The current study identified CDK12 mRNA and protein expression remarkably upregulated in CC patients. Upregulated CDK12 was closely associated with CC progression and poor prognosis. In vitro and in vivo functional experiments showed that knockdown of CDK12 inhibited cancer cell proliferation and colony formation and promoted apoptosis. Further investigations demonstrated that CDK12 regulated the immune microenvironment to facilitate the progression of CC cells by promoting macrophage infiltration. Meanwhile, we first demonstrated that nuclear import of CDK12 is mediated by TNPO1 and might be a new therapeutic target in oncology. Collectively, this study pointed out the potential of CDK12 to serve as a novel therapeutic target in restricting CC proliferation and cell cycle process through promoting macrophage infiltration.

Intraoperative frozen pathology exam of Common iliac lymph nodes and Para-Aortic lymphadenectomy on the prognosis and quality of life for patients with IB2-IIA2 Cervical Cancer: trial protocol for a randomized controlled trial (C-PACC trial)

The impact of para-aortic lymphadenectomy (PALD) on prognosis and quality of life (QoL) for IB2-IIA2 cervical cancer patients remain controversial. And whether intraoperative frozen pathology exam on common iliac lymph nodes could help predict para-aortic lymph node (PALN) metastasis was unanswered with high-level evidence. A multi-center, randomized controlled study is intended to investigate the effect of PALD on the prognosis and QoL in cervical cancer patients and to assess the value of intraoperative frozen pathological evaluation of common iliac nodes metastasis for the prediction of PALN metastasis. After choosing whether to receive intraoperative frozen pathological examination of bilateral common iliac lymph nodes, eligible patients will be randomly assigned (1:1) to receive PALD or not. The primary end point is 2-year progression-free survival (PFS). The secondary end points include 5-year PFS, 2-year overall survival (OS), 5-year OS, adverse events (AEs) caused by PALD, AEs caused by radiotherapy and QoL. A total of 728 patients will be enrolled from 8 hospitals in China within 3-year period and followed up for 5 years. Chinese Clinical Trial Register Identifier: ChiCTR2000035668.

Surgery and Niraparib in Secondary Recurrent Ovarian Cancer (SOC-3 Trial)

This is a Phase II, open-label, multicenter, randomized umbrella study to evaluate the efficacy of cytoreductive surgery and Niraparib maintenance in participants with platinum-sensitive secondary recurrent ovarian cancer. Cohort 1 will focus on participants without prior use of PARP inhibitor, and without prior secondary cytoreduction (SCR) when first recurrence. Cohort 2 will focus on participants with prior use of PARP inhibitor, but without prior SCR when first recurrence. Cohort 3 will focus on participants with SCR when first recurrence, but without prior use of PARP inhibitor.