A non-canonical role of the inner kinetochore in regulating sister-chromatid cohesion at centromeres.

The 16-subunit Constitutive Centromere-associated Network (CCAN)-based inner kinetochore is well-known for connecting centromeric chromatin to the spindle-binding outer kinetochore. Here, we report a non-canonical role for the inner kinetochore in directly regulating sister-chromatid cohesion at centromeres. We provide biochemical, X-ray crystal structure, and intracellular ectopic localization evidence that the inner kinetochore directly binds cohesin, a ring-shaped multi-subunit complex that holds sister chromatids together from S-phase until anaphase onset. This interaction is mediated by binding of the 5-subunit CENP-OPQUR sub-complex of CCAN to the Scc1-SA2 sub-complex of cohesin. Mutation in the CENP-U subunit of the CENP-OPQUR complex that abolishes its binding to the composite interface between Scc1 and SA2 weakens centromeric cohesion, leading to premature separation of sister chromatids during delayed metaphase. We further show that CENP-U competes with the cohesin release factor Wapl for binding the interface of Scc1-SA2, and that the cohesion-protecting role for CENP-U can be bypassed by depleting Wapl. Taken together, this study reveals an inner kinetochore-bound pool of cohesin, which strengthens centromeric sister-chromatid cohesion to resist metaphase spindle pulling forces.

Cancer-associated fibroblasts: a versatile mediator in tumor progression, metastasis, and targeted therapy.

Tumor microenvironment (TME) has been demonstrated to play a significant role in tumor initiation, progression, and metastasis. Cancer-associated fibroblasts (CAFs) are the major component of TME and exhibit heterogeneous properties in their communication with tumor cells. This heterogeneity of CAFs can be attributed to various origins, including quiescent fibroblasts, mesenchymal stem cells (MSCs), adipocytes, pericytes, endothelial cells, and mesothelial cells. Moreover, single-cell RNA sequencing has identified diverse phenotypes of CAFs, with myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs) being the most acknowledged, alongside newly discovered subtypes like antigen-presenting CAFs (apCAFs). Due to these heterogeneities, CAFs exert multiple functions in tumorigenesis, cancer stemness, angiogenesis, immunosuppression, metabolism, and metastasis. As a result, targeted therapies aimed at the TME, particularly focusing on CAFs, are rapidly developing, fueling the promising future of advanced tumor-targeted therapy.

Histone H2A phosphorylation recruits topoisomerase IIα to centromeres to safeguard genomic stability.

Chromosome segregation in mitosis requires the removal of catenation between sister chromatids. Timely decatenation of sister DNAs at mitotic centromeres by topoisomerase IIα (TOP2A) is crucial to maintain genomic stability. The chromatin factors that recruit TOP2A to centromeres during mitosis remain unknown. Here, we show that histone H2A Thr-120 phosphorylation (H2ApT120), a modification generated by the mitotic kinase Bub1, is necessary and sufficient for the centromeric localization of TOP2A. Phosphorylation at residue-120 enhances histone H2A binding to TOP2A in vitro. The C-gate and the extreme C-terminal region are important for H2ApT120-dependent localization of TOP2A at centromeres. Preventing H2ApT120-mediated accumulation of TOP2A at mitotic centromeres interferes with sister chromatid disjunction, as evidenced by increased frequency of anaphase ultra-fine bridges (UFBs) that contain catenated DNA. Tethering TOP2A to centromeres bypasses the requirement for H2ApT120 in suppressing anaphase UFBs. These results demonstrate that H2ApT120 acts as a landmark that recruits TOP2A to mitotic centromeres to decatenate sister DNAs. Our study reveals a fundamental role for histone phosphorylation in resolving centromere DNA entanglements and safeguarding genomic stability during mitosis.

Oncogenic HPV promotes the expression of the long noncoding RNA lnc-FANCI-2 through E7 and YY1.

Long noncoding RNAs (lncRNAs) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remain unknown. By RNA-sequencing (RNA-seq) analyses of 18 clinical specimens and selective validation by RT-qPCR analyses of 72 clinical samples, we provide evidence that, relative to normal cervical tissues, 194 lncRNAs are differentially regulated in high-risk (HR)-HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, is extensively characterized because it is expressed from a genomic locus adjacent to the FANCI gene encoding an important DNA repair factor. Both genes are up-regulated in HPV lesions and in in vitro model systems of HR-HPV18 infection. We observe a moderate reciprocal regulation of lnc-FANCI-2 and FANCI in cervical cancer CaSki cells. In these cells, lnc-FANCI-2 is transcribed from two alternative promoters, alternatively spliced, and polyadenylated at one of two alternative poly(A) sites. About 10 copies of lnc-FANCI-2 per cell are detected preferentially in the cytoplasm. Mechanistically, HR-HPVs, but not low-risk (LR)-HPV oncogenes induce lnc-FANCI-2 in primary and immortalized human keratinocytes. The induction is mediated primarily by E7, and to a lesser extent by E6, mostly independent of p53/E6AP and pRb/E2F. We show that YY1 interacts with an E7 CR3 core motif and transactivates the promoter of lnc-FANCI-2 by binding to two critical YY1-binding motifs. Moreover, HPV18 increases YY1 expression by reducing miR-29a, which targets the 3' untranslated region of YY1 mRNA. These data have provided insights into the mechanisms of how HR-HPV infections contribute to cervical carcinogenesis.

Secondary cytoreduction surgery for recurrent epithelial ovarian cancer patients after PARPi maintenance: A multicenter, randomized, controlled clinical trial.

BACKGROUND: Poly ADP-ribose polymerase inhibitors (PARPi) treatment has radically changed the treatment strategy for epithelial ovarian cancer. Cancer progression with PARPi maintenance is a new problem that has arisen in clinical practice, and the value of secondary cytoreduction surgery remains unknown. PRIMARY OBJECTIVE: To evaluate the benefits of secondary cytoreductive surgery and to clarify the sensitivity to platinum in patients with firstline or secondline recurrent epithelial ovarian cancer who have completed ≥6 months of PARPi maintenance. STUDY HYPOTHESIS: Carefully selected patients who progress on PARPi maintenance will benefit from secondary cytoreductive surgery. TRIAL DESIGN: This is a multicenter phase III trial. Eligible patients will be randomly assigned at a ratio of 1:1 to either the experimental or standard arm. Patients in the experimental arm will receive secondary cytoreductive surgery followed by platinum based chemotherapy, while patients in the standard arm will be provided with chemotherapy alone. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients diagnosed with firstline or secondline recurrent epithelial ovarian cancer who had previously received ≥4 cycles of platinum based chemotherapy in initial treatment followed by PARPi maintenance therapy for ≥6 months prior to recurrence. PRIMARY ENDPOINT: Progression free survival. SAMPLE SIZE: 400 patients. ESTIMATED DATES FOR COMPETING ACCRUAL AND PRESENTING RESULTS: Accrual completion is expected in December 2024 with results mature after 2 years of follow-up in 2026. TRIAL REGISTRATION: ClinicalTrials.gov NCT05607329.

Ovarian Metastasis by Gastric-type Endocervical Adenocarcinoma: A Clinicopathologic Description of 12 Cases.

Cervical gastric-type adenocarcinoma has a propensity for ovarian metastasis, but the clinicopathologic findings and possible routes of tumor spread have not been well characterized to date. To address these points, we reported 12 cervical gastric-type adenocarcinomas with ovarian metastases from a single institution. Seven patients with gastric-type adenocarcinoma had concurrent endometrial fallopian tube involvement, 5 of which showed tumors confined to the fallopian tube mucosa. Two of these 5 patients died of disease at 2 and 16 mo, and 1 recurred at 18 mo. In the remaining 5 patients, 3 had wide pelvic/peritoneal spread while the other 2 showed no evidence of uterine or tubal involvement. Among them, 1 died of disease at 94 mo, and another relapsed at 20 mo. Morphologically, ovarian tumors frequently had surface involvement consistent with metastasis, but also mimicked a primary tumor with a mixture of benign/borderline/intraepithelial carcinoma-like areas, as well as carcinoma with expansile or destructive stromal invasion. The tubal lesions were predominantly in the form of mucosal colonization without invasion of the underlying structures. Block p16 and high-risk human papillomavirus mRNA signals were not detected in cervical gastric-type adenocarcinomas and ovarian metastatic tumors. We conclude that fallopian tube spread may be associated with ovarian metastasis of cervical gastric-type adenocarcinomas that have bad clinical outcomes. Ovarian involvement may be a part of the aggressive nature of these tumors.

Microenvironment remodeled by tumor and stromal cells elevates fibroblast-derived COL1A1 and facilitates ovarian cancer metastasis.

Wide peritoneal metastasis is the cause of the highest lethality of ovarian cancer in gynecologic malignancies. Ascites play a key role in ovarian cancer metastasis, but involved mechanism is uncertain. Here, we performed a quantitative proteomics of ascites, and found that collagen type I alpha 1 (COL1A1) was notably elevated in ascites from epithelial ovarian cancer patients compared to normal peritoneal fluids, and verified that elevated COL1A1 was mainly originated from fibroblasts. COL1A1 promoted migration and invasion of ovarian cancer cells, but such effects were partially eliminated by COL1A1 antibodies. Intraperitoneally injected COL1A1 accelerated intraperitoneal metastasis of ovarian cancer xenograft in NOD/SCID mice. Further, COL1A1 activated downstream AKT phosphorylation by binding to membrane surface receptor integrin ß1 (ITGB1). Knockdown or blockage of ITGB1 reversed COL1A1 enhanced migration and invasion in ovarian cancer cells. Conversely, ovarian cancer ascites and fibrinogen promoted fibroblasts to secrete COL1A1. Elevated fibrinogen in ascites might be associated with increased vascular permeability induced by ovarian cancer. Our findings suggest that microenvironment remodeled by tumor cells and stromal cells promotes fibroblasts to secrete COL1A1 and facilitates the metastasis of ovarian cancer, which may provide a new approach for ovarian cancer therapeutics.

Transcriptome sequencing profiles of cervical cancer tissues and SiHa cells.

High-risk human papillomavirus (HPV) is a causal factor for cervical cancer, of which HPV16 is the predominant genotype, but the detailed mechanism remains to be elucidated. In this study, we performed transcriptome sequencing in cervical cancer tissues with HPV16-positive and normal tissues with HPV16-negative, and SiHa cells with or without HPV16 E6/E7 knockdown, and identified 140 differential expressed genes (DEGs) in two data sets. We carried out a series of bioinformatic analyses to learn more about the 140 DEGs, and found that 140 DEGs were mostly enriched in cell cycle and DNA repair through Kyoto Encyclopedia of Genes and Genomes pathway enrichment, Gene Ontology annotation, and gene set enrichment analysis. A total of 20 genes including RMI1, MKI67, FANCB, KIF14, CENPI, RACGAP1, EXO1, KIF4A, FOXM1, C19orf57, PSRC1, NUSAP1, CIT, NDC80, MCM7, GINS2, MCM6, ORC1, TLX2, and UHRF1 were screened by co-expression analysis; of those, the expressions of 6 (CENPI, FANCB, KIF14, ORC1, RACGAP1, and RMI1) were verified by qRT-PCR. Further, we found that E2F family, NF-Y, AhR:Arnt, and KROX family may be involved in modulating DEGs by TransFind prediction. TF2DNA database and co-expression analysis suggested that 12 TFs (ZNF367, TLX2, DEPDC1B, E2F8, ZNF541, EGR2, ZMAT3, HES6, CEBPA, MYBL2, FOXM1, and RAD51) were upstream modulators of DEGs. Our findings may provide a new understanding for effects of HPV oncogenes in the maintenance of cancerous state at the transcriptional level.

Cyclin-dependent kinase 9 promotes cervical cancer development via AKT2/p53 pathway.

Aberrant activation of cyclin-dependent kinase 9 (CDK9) is widespread in human cancers. However, the underlying mechanisms of CDK9 activation and the therapeutic potential of CDK9 inhibition in cervical cancer remain largely unknown. Here, we report that CDK9 is gradually upregulated during cervical lesion progression and regulated by HPV16 E6. CDK9 levels are highly correlated with FIGO stage, pathological grade, deep-stromal invasion, tumor size, and lymph nodes metastasis. Knockdown of CDK9 by specific siRNA inhibits cervical cancer cell proliferation in vitro, as well as tumorigenesis in vivo. CDK9 inhibition causes a significant decreased AKT2 and increased p53 protein expression revealing novel CDK9-regulatory mechanisms. Overexpression of AKT2 rescued the suppressive effects caused by CDK9 knockdown, suggesting that AKT2 induction is essential for CDK9-induced transformation. Moreover, CDK9 expression was positively correlated with AKT2 and negatively correlated with p53 in cervical cancer tissues with HPV16 infection. Our findings demonstrate for the first time that CDK9 acts as a proto-oncogene in cervical cancer, modulating cell proliferation and apoptosis through AKT2/p53 pathway. Therefore, our data provide novel mechanistic insights into the role of CDK9 in cervical cancer development. © 2018 IUBMB Life, 71(3):347-356, 2019.

Micro ribonucleic acid-93 promotes oncogenesis of cervical cancer by targeting RAB11 family interacting protein 1.

AIM: Micro ribonucleic acid (RNA)-93 (miR-93) is a novel oncogenic miRNA dysregulated in many types of tumors. We aimed to further study the expression pattern and clinical significance of miR-93 and its target, the RAB11 family interacting protein 1 (RAB11FIP1) gene, in cervical cancer. METHODS: Mir-93 and RAB11FIP1 expression in cervical cancer (n = 168), cervical intraepithelial neoplasia (CIN) 2 or 3 (n = 60) and normal cervical tissues (n = 48) was examined by real-time reverse transcription polymerase chain reaction and immunohistochemical staining. Methyl thiazolyl tetrazolium assay, flow cytometry, and Transwell chamber invasion assay were performed to investigate the function of miR-93 in the proliferation, apoptosis and invasion of cervical cancer cell lines SiHa and CaSki. Luciferase activity assay was conducted to identify the target gene of miR-93. RESULTS: Mir-93 expression levels in cervical cancer and CIN tissues were significantly increased (P = 0.032), but the RAB11FIP1 protein was significantly decreased (P = 0.006) compared with normal tissues. Neither was associated with clinicopathological variables. Enforced miR-93 knockdown or RAB11FIP1 overexpression suppressed proliferation and promoted apoptosis, but did not influence invasion in cervical cancer cells. Luciferase activity indicated that RAB11FIP1 was a direct target for miR-93. CONCLUSIONS: Our findings suggest that overexpression of miR-93 via targeting RAB11FIP1 as an early event plays an important role in oncogenesis of cervical cancer. MiR-93 and its target protein RAB11FIP1 may be potential therapeutic targets for cervical cancer and its precursors.

[Expression of miR-let-7e-3p in cervical intraepithelial neoplasm and cervix carcinoma and its clinical significance].

Objective: To investigate the expression of microRNA (miRNA, miR) let-7e-3p in different cervical lesions and its clinical significance. Methods: The expression of miR-let-7e-3p in the tissues of normal cervix (n=26), high-grade squamous intraepithelial lesion (HSIL) (n=37), and cervix carcinoma (n=101) were detected by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). The correlation of miR-let-7e-3p expression with the clinicopathological parameters of patients with cervical cancer was analyzed. miR-let-7e-3p mimic was transfected into cervical carcinoma Siha cells. The cell cycle and apoptosis were determined by flow cytometry; cell proliferation was determined by CCK-8 kit; and the migration and invasion of cells were determined by Transwell assay. Results: The relative expression levels of miR-let-7e-3p in normal cervix, HSIL, and cervical carcinoma were 1.45±0.24, 0.79±0.05 and 0.46±0.04, respectively (all P<0.05). After transfection with miR-let-7e-3p mimic, the S-phase fraction and apoptosis rate of Siha cells were increased significantly compared with control group[(29.76±6.6)% vs (13.38±1.3)%, P<0.05; (5.98±1.38)% vs (3.53±0.79)%, P<0.05, respectively]. OD of transfected Siha cells at 48, 72 and 96 h were 0.57±0.11,0.65±0.04 and 0.84±0.14, which were significantly lower than those of untransfected Siha cells (0.74±0.05, 0.93±0.10 and 1.47±0.14, all P<0.05). The migration and invasion abilities of transfected Siha cells were not significantly changed (all P>0.05). Conclusion: The expression of miR-let-7e-3p is down-regulated in cervical neoplasms, which is associated with cell cycle arrest and proliferation inhibition of cervical cancer cells.

[Distribution of human papillomavirus genotypes in early-stadge cervical adenocarcinoma and its clinical significance].

OBJECTIVE: To explore the distribution of high-risk HPV-genotypes in early-stage cervical adenocarcinoma and understand the clinical significance of HPV genotyping. METHODS: From June 2000 to May 2010, a total of 101 paraffin surgical specimens of cervical adenocarcinoma were genotyped by nested polymerase chain reaction (nested PCR). The associations of HPV18 with clinicopathological parameters and survival were further analyzed. RESULTS: DNA extraction was successfully performed for 96 samples. The HPV-positive rate of early-stage cervical adenocarcinoma was 95.8% (92/96). Two common HPV types were HPV16 (59.4%) and HPV18 (60.4%). The prevalence rates of single, double and multiple HPV infections were 22.9%, 32.3% and 40.6% respectively. The positive rates of lymph node metastasis and vascular involvement with HPV18 infection were 27.6% and 22.4% versus 7.9% and 7.9% for those without HPV18 infection.Univariate analysis showed that positive surgical margin, uterine corpus invasion, lymph node metastasis and HPV18 infection were the predictive factors for poor prognosis of patients with cervical adenocarcinoma. Multivariate analysis revealed that lymph node metastasis was an independent prognostic factor for both disease-free and overall survivals. And uterine corpus invasion was an independent prognostic factor of overall survival for early-stage cervical adenocarcinoma patients. CONCLUSION: HPV16 and HPV18 are major types responsible for early-stage cervical adenocarcinoma.Infection with HPV18 is prone to lymph node metastasis and vascular involvement.However, there is no correlation with disease-free survival or overall survival.

Evaluation of secondary cytoreduction surgery in platinum-resistant ovarian cancer patients within three-line recurrent: a multicenter, randomized controlled study.

BACKGROUND: Epithelial ovarian cancer is the leading cause of death among gynecological malignancies. Platinum resistance remains a dilemma and bottleneck in treatment, and salvage chemotherapy has limited effectiveness. Recently, the role of secondary cytoreductive surgery (SCS) in patients with platinum-resistant recurrent ovarian cancer (ROC) has caused attention especially in patients with oligometastases. However, there is neither high-quality evidence-based evidence nor standardized criteria for selecting SCS for patients with platinum-resistant ROC until now. METHODS: This multicenter, randomized, controlled clinical trial is to evaluate the value of SCS and to clarify reliable criteria of utilizing SCS in women with ROC, which is led by Gynecologic Oncology Group, Women's Hospital, Zhejiang University School of Medicine. Recruitment has started on January 1st, 2023, and is scheduled to end in December 2026. One hundred and forty participants with platinum-resistant ROC who meet the "RSCS criteria" will be randomized assigned at a ratio of 1:1 to either the experimental arm or the standard arm. Patients in the experimental arm will receive SCS followed by non-platinum single agent chemotherapy (paclitaxel, gemcitabine or liposomal adriamycin) for at least 4 cycles while patients in the standard arm will be provided with only non-platinum single agent chemotherapy. The primary outcome is progression-free survival. The secondary outcomes are overall survival, adverse events and health-related cancer-specific quality of life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05633199.

Single-cell transcriptomics reveals the aggressive landscape of high-grade serous carcinoma and therapeutic targets in tumor microenvironment.

High-grade serous carcinoma (HGSC) is characterized by early abdominal metastasis, leading to a dismal prognosis. In this study, we conducted single-cell RNA sequencing on 109,573 cells from 34 tumor samples of 18 HGSC patients, including both primary tumors and their metastatic sites. Our analysis revealed a distinct S100A9+ tumor cell subtype present in both primary and metastatic sites, strongly associated with poor overall survival. This subtype exhibited high expression of S100A8, S100A9, ADGRF1, CEACAM6, CST6, NDRG2, MUC4, PI3, SDC1, and C15orf48. Individual knockdown of these ten marker genes, validated through in vitro and in vivo models, significantly inhibited ovarian cancer growth and invasion. Around S100A9+ tumor cells, a population of HK2+_CAF was identified, characterized by activated glycolysis metabolism, correlating with shorter overall survival in patients. Notably, similar to CAFs, immunosuppressive tumor-associated macrophage (TAM) subtypes underwent glycolipid metabolism reprogramming via PPARgamma regulation, promoting tumor metastasis. These findings shed light on the mechanisms driving the aggressiveness of HGSC, offering crucial insights for the development of novel therapeutic targets against this formidable cancer.

RAD51B-AS1 promotes the malignant biological behavior of ovarian cancer through upregulation of RAD51B. / RAD51B-AS1通过上调RAD51B促进卵巢癌的恶性生物学行为.

Long non-coding RNAs (lncRNAs) play an indispensable role in the occurrence and development of ovarian cancer (OC). However, the potential involvement of lncRNAs in the progression of OC is largely unknown. To investigate the detailed roles and mechanisms ofRAD51 homolog B-antisense 1 (RAD51B-AS1), a novel lncRNA in OC, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to verify the expression of RAD51B-AS1. Cellular proliferation, metastasis, and apoptosis were detected using the cell counting kit-8 (CCK-8), colony-formation, transwell, and flow cytometry assays. Mouse xenograft models were established for the detection of tumorigenesis. The results revealed that RAD51B-AS1 was significantly upregulated in a highly metastatic human OC cell line and OC tissues. RAD51B-AS1 significantly increased the proliferation and metastasis of OC cells and enhanced their resistance to anoikis. Biogenetics prediction analysis revealed that the only target gene of RAD51B-AS1 was RAD51B. Subsequent gene function experiments revealed that RAD51B exerts the same biological effects as RAD51B-AS1. Rescue experiments demonstrated that the malignant biological behaviors promoted by RAD51B-AS1 overexpression were partially or completely reversed by RAD51B silencing in vitro and in vivo. Thus, RAD51B-AS1 promotes the malignant biological behaviors of OC and activates the protein kinase B (Akt)/B cell lymphoma protein-2 (Bcl-2) signaling pathway, and these effects may be associated with the positive regulation of RAD51B expression. RAD51B-AS1 is expected to serve as a novel molecular biomarker for the diagnosis and prediction of poor prognosis in OC, and as a potential therapeutic target for disease management.

Advances in immunotherapy for gynecological malignancies.

To date, surgery, chemotherapy and radiotherapy are mainly used to treat or remove gynecological malignancies. However, these approaches have their limitations when facing complicated female diseases such as advanced cervical and endometrial cancer (EC), chemotherapy-resistant gestational trophoblastic neoplasia and platinum-resistant ovarian cancer. Instead, immunotherapy, as an alternative, could significantly improve prognosis of those patients receiving traditional treatments, with better antitumor activities and possibly less cellular toxicities. Its' development is still not fast enough to meet the current clinical needs. More preclinical studies and larger-scale clinical trials are required. This review aims to introduce the landscape and up-to-date status of immunotherapy against gynecological malignancies, with a discussion of the challenges and future direction.

Nanoengineered Gallium Ion Incorporated Formulation for Safe and Efficient Reversal of PARP Inhibition and Platinum Resistance in Ovarian Cancer.

Platinum-based chemotherapy remains the main systemic treatment of ovarian cancer (OC). However, the inevitable development of platinum and poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) resistance is associated with poor outcomes, which becomes a major obstacle in the management of this disease. The present study developed "all-in-one" nanoparticles that contained the PARPi olaparib and gallium (Ga) (III) (olaparib-Ga) to effectively reverse PARPi resistance in platinum-resistant A2780-cis and SKOV3-cis OC cells and in SKOV3-cis tumor models. Notably, the olaparib-Ga suppressed SKOV3-cis tumor growth with negligible toxicity. Moreover, the suppression effect was more evident when combining olaparib-Ga with cisplatin or carboplatin, as evaluated in A2780-cis and SKOV3-cis cells. Mechanistically, the combined treatment induced DNA damage, which elicited the activation of ataxia telangiectasia mutated (ATM)/AMT- and Rad3-related (ATR) checkpoint kinase 1 (Chk1)/Chk2 signal transduction pathways. This led to the arrest of cell cycle progression at S and G2/M phases, which eventually resulted in apoptosis and cell death due to unrepairable DNA damage. In addition, effective therapeutic responses to olaparib-Ga and cisplatin combination or olaparib-Ga and carboplatin combination were observed in SKOV3-cis tumor-bearing animal models. Altogether, the present findings demonstrate that olaparib-Ga has therapeutic implications in platinum-resistant OC cells, and the combination of olaparib-Ga with cisplatin or carboplatin may be promising for treating patients with OC who exhibit resistance to both PARPi and platinum.

miR-375 is down-regulated in squamous cervical cancer and inhibits cell migration and invasion via targeting transcription factor SP1.

Pelvic lymph node metastases are regarded as the most important risk factor and a predictor of poor prognosis for patients with cervical cancer. Exploration of metastasis-related molecules is helpful toward improving the prognosis in cervical cancer. To identify the role of miR-375 in metastasis and progression of cervical cancer, we examined the expression of miR-375 in 170 cervical cancer tissues and 68 normal cervical tissues, using stem-loop quantitative PCR, and found that the expression of miR-375 in cervical cancer tissues was significantly decreased by 4.45-fold, compared with 68 normal tissues. A significant correlation existed between miR-375 expression and clinicopathologic parameters, including lymph node metastasis of cervical cancer. Overexpressed miR-375 suppressed cell proliferation, blocked G1-to-S cell-cycle transition, and inhibited cell migration and invasion in human cervical SiHa and CaSki cells. SP1, a potential target gene of miR-375, was inversely correlated with miR-375 expression in cervical cancer tissues. Moreover, SP1 was negatively regulated by miR-375, and knockdown of SP1 by siRNA inhibited cell malignant behaviors. Thus, our findings suggest that down-regulated miR-375 promotes cell malignant behaviors via the target gene SP1 and may consequently contribute to the progression of cervical cancer.

Progressive miRNA expression profiles in cervical carcinogenesis and identification of HPV-related target genes for miR-29.

miRNAs have the potential to act on diverse downstream genes, and miRNA signatures of HPV-infected tissues may provide insight into HPV-related carcinogenesis. We set out to profile miRNA expression in HPV-infected samples and relate this to histological and grade-specific alterations in the spectrum of cervical carcinogenesis in vivo. A total of 31 miRNAs showed significant and continuous expression along with the progression from normal cervical tissue to cancer, and six of them were validated in 133 samples. By bioinformatics analyses, we established a putative HPV-associated miRNA-mRNA regulatory network, showing that miR-29 is the most highly enriched. We also found that YY1 and CDK6 were both positively correlated with E6/E7 RNA expression and targeted by tumour-suppressive miR-29. Evidence of miR-29 involvement in HPV infection was further verified in patient samples and by various experimental approaches. Taken together, our results suggest that HPVs have oncogenic properties at least in part by reshaping the milieu of cellular miRNAs. miR-29 restrains cell cycle progression and induces apoptosis via YY1 and CDK6 promoting malignant transformation induced by HPV, although the abnormality of miR-29 in HPV-infected cells might be regulated in an indirect way.

Modified Intraperitoneal Chemotherapy Without Bevacizumab as a First-Line Therapy for Newly Diagnosed Advanced Epithelial Ovarian Cancer-Two Centers Experiences.

Objectives: To evaluate whether the modified intraperitoneal plus intravenous chemotherapy regimen as a first-line therapy for advanced epithelial ovarian cancer (EOC) in China can be well-tolerated or confer any potential benefit on survival. Methods: We evaluated the outcomes of women with newly diagnosed advanced-stage III-IV EOC treated with optimal cytoreductive surgery (<1 cm) and subsequent intraperitoneal plus intravenous chemotherapy or intravenous chemotherapy from January 2005 to December 2017 at two Gynecologic Oncology Centers in China. Kaplan-Meier survival analysis and Cox regression multivariate analysis models were performed to determine the toxicities and survival outcomes. Results: A total of 463 patients with stage III-IV EOC were enrolled. According to the propensity scores (1:2), 85 patients who received intraperitoneal plus intravenous chemotherapy (group A) were matched to 170 patients who received intravenous chemotherapy (group B). The median follow-up time was 41 months (range 6-155 months). However, there was no statistically significant difference in the median progression-free survival (PFS) (20 vs. 22 months, P = 0.351) or 3-year overall survival (OS) rate (80 vs. 78%, P = 0.749) between the two groups. R0 primary cytoreductive surgery was the only factor related to PFS (P = 0.028) and OS (P = 0.005) by Cox regression analysis. The incidence of grade 3/4 adverse events did not significantly differ between the two groups. Conclusion: The efficacy of intraperitoneal chemotherapy mainly comes from the intraperitoneal drug dose intensity and cumulative dose. High-efficiency and low-toxicity intraperitoneal chemotherapy regimens still need to be found and validated.