Publications by authors named "Beihua Kong"

201 Publications

Enhanced Recovery After Surgery Impact on the Systemic Inflammatory Response of Patients Following Gynecological Oncology Surgery: A Prospective Randomized Study.

Cancer Manag Res 2021 1;13:4383-4392. Epub 2021 Jun 1.

Department of Obstetrics and Gynecology, Qilu hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.

Objective: Enhanced recovery after surgery (ERAS) protocol has widely gained acceptance in gynecological surgery. Its safety and efficacy should be evaluated fully via well-designed, randomized, control trials. The main objective of our study is to compare the ERAS protocol with the conventional perioperative care program after gynecological oncology. Furthermore, the secondary objectives of our study are the identification of markers that allow us to evaluate the effectiveness of the application of ERAS elements in the modulation of the body's response to surgical stress.

Methods: Patients with gynecological tumors indicated for surgery were randomly assigned to either the ERAS group or the conventional group. The ERAS protocol included short fasting time, fluid restriction, early oral feeding, reduced opioid consumption and immediate mobilization after surgery. The primary endpoint was the reduction of hospital stay in the ERAS group. The day of first flatus, postoperative nausea and vomiting (PONV), maximum pain score by the visual analogue scale (VAS) and complication, readmission rate, reoperation rate, postoperative mortality, total hospital cost and systemic inflammatory response (SIR) were secondary endpoints.

Results: A total of 130 patients in gynecological tumor surgery were enrolled (ERAS = 65, conventional = 65). The ERAS group had faster bowel function recovery, significantly less pain, less PONV, shorter hospital stay, and less total hospital costs. SIR markers were estimated and screened out that postoperative platelet, neutrophil-lymphocyte-ratio (NLR) and platelet-lymphocyte-ratio (PLR) were significantly lower in ERAS groups compared to conventional groups.

Conclusion: The implementation of ERAS protocol is safe and enhances postoperative recovery after gynecological oncology surgery. We firstly reveal the beneficial effect of ERAS protocols on the alleviation of postoperative SIR, which is a reflection of the magnitude of surgical trauma. Postoperative platelet, NLR or PLR could be the novel and inexpensive markers to assess how ERAS protocols modulate gynecological oncology surgery.

Trial Registration: The trial was registered in ClinicalTrials.gov (NCT03629626).
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http://dx.doi.org/10.2147/CMAR.S294718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179735PMC
June 2021

Progress in the management of ovarian granulosa cell tumor: A review.

Acta Obstet Gynecol Scand 2021 May 24. Epub 2021 May 24.

Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

Ovarian granulosa cell tumor (GCT) is a rare, low-grade malignant tumor that accounts for 70% of the sex cord-stromal tumors, it has two histopathological types with different clinical and biological features: adult GCT and juvenile GCT. Most women diagnosed with the adult GCT have a favorable prognosis, with a 5-year survival rate of 97-98%, but adult GCT has a feature of late relapse, the recurrence time could be more than 20 years after diagnosis. Juvenile GCT had a survival rate of 97% in stage I and a 5-year survival rate of 0%-22% in advanced stage with earlier relapse than adult GCT. Consequently, the scenario emphasizes the need for early diagnosis, standardized treatment protocols and long-term follow-up. However, there is a lack of consensus regarding accurate diagnosis of GCT and adjuvant treatment. Furthermore, GCT tends to occur in young women, which emphasizes the viability of fertility-sparing surgery. The current review performed a systematic literature review of 60 articles in order to summarize the latest advancements of GCT, with an emphasis on the molecular pathogenesis and survival after fertility-sparing surgery. We found that young women with fertility-sparing surgery had a desirable reproductive and survival outcome compared to radical surgery.
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http://dx.doi.org/10.1111/aogs.14189DOI Listing
May 2021

MiR-501 promotes tumor proliferation and metastasis by targeting HOXD10 in endometrial cancer.

Cell Mol Biol Lett 2021 May 22;26(1):20. Epub 2021 May 22.

Key Laboratory of Gynecologic Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, People's Republic of China.

Background: Several studies have shown the crucial role of miR-501 in regulating cellular pathology in various cancers. However, the function and expression of miR-501 in endometrial cancer (EC) remain obscure.

Methods: The expression of miR-501 was determined using quantitative real-time PCR. MTT assay, colony formation assay and cell cycle analysis were used to evaluate the proliferation ability. Migration and invasion were assessed using transwell assay. Tumor formation in nude mice was used to observe the effects of miR-501 on cell proliferation and migration in vivo. Luciferase assay, quantitative real-time PCR and western blot were applied to determine that HOXD10 was the target gene of miR-501.

Results: In this study, we observed significantly up-regulated expression of miR-501 in endometrial cancer, which correlated with higher pelvic lymph node metastasis and shorter overall survival in high-grade endometrial cancer. High expression of miR-501 was also found in the copy-number-high group than other groups. Moreover, in vitro and in vivo assay showed that overexpression of miR-501 can promote proliferation and metastasis. Mechanistically, we found that miR-501 promotes tumor progression by directly targeting HOXD10. Further study also indicated that miR-501 overexpression can activate the AKT/mTOR pathway.

Conclusions: MiR-501, which functions as an oncomir in endometrial cancer, might be a potential therapeutic target in high grade endometrial cancer.
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http://dx.doi.org/10.1186/s11658-021-00268-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141179PMC
May 2021

Hyperemesis gravidarum induced refeeding syndrome causes blood cell destruction: a case report and literature review.

BMC Pregnancy Childbirth 2021 May 9;21(1):366. Epub 2021 May 9.

Department of Obstetrics Gynecology, Cheeloo College of Medicine, Qilu Hospital, Shandong University, Shandong, 250012, Jinan, China.

Background: Hyperemesis gravidarum (HG) is a common complication during pregnancy, however, HG associated simultaneous onset of blood cell destruction due to electrolyte abnormalities is rare. In this case, a woman with refeeding syndrome (RFS) secondary to electrolyte abnormalities caused by severe HG was diagnosed and managed in our hospital.

Case Presentation: A 29-year old woman was sent to the local hospitals because of severe HG with appetite loss, weight reduction, general fatigue, and she was identified to have severe electrolyte abnormalities. However, the electrolyte abnormalities were not corrected promptly, and then she had the symptoms of stillbirth, altered mental status, visual hallucination, hemolytic anemia and thrombocytopenia. After transferred to our hospital, we continued to correct the electrolyte abnormalities and the labor induction was performed as soon as possible. The symptoms of blood cell destruction were relieved obviously, and the patient discharged four days later. The electrolyte disturbances and physio-metabolic abnormalities caused by HG helped us diagnose this case as RFS.

Conclusions: This case emphasizes that patients with RFS should be diagnosed appropriately and intervened promptly in order to prevent electrolyte imbalance induced blood cell destruction.
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http://dx.doi.org/10.1186/s12884-021-03821-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108454PMC
May 2021

Light scattering pattern specific convolutional network static cytometry for label-free classification of cervical cells.

Cytometry A 2021 Jun 22;99(6):610-621. Epub 2021 Apr 22.

School of Microelectronics, Shandong University, Jinan, China.

Cervical cancer is a major gynecological malignant tumor that threatens women's health. Current cytological methods have certain limitations for cervical cancer early screening. Light scattering patterns can reflect small differences in the internal structure of cells. In this study, we develop a light scattering pattern specific convolutional network (LSPS-net) based on deep learning algorithm and integrate it into a 2D light scattering static cytometry for automatic, label-free analysis of single cervical cells. An accuracy rate of 95.46% for the classification of normal cervical cells and cancerous ones (mixed C-33A and CaSki cells) is obtained. When applied for the subtyping of label-free cervical cell lines, we obtain an accuracy rate of 93.31% with our LSPS-net cytometric technique. Furthermore, the three-way classification of the above different types of cells has an overall accuracy rate of 90.90%, and comparisons with other feature descriptors and classification algorithms show the superiority of deep learning for automatic feature extraction. The LSPS-net static cytometry may potentially be used for cervical cancer early screening, which is rapid, automatic and label-free.
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http://dx.doi.org/10.1002/cyto.a.24349DOI Listing
June 2021

Splicing factor USP39 promotes ovarian cancer malignancy through maintaining efficient splicing of oncogenic HMGA2.

Cell Death Dis 2021 Mar 17;12(4):294. Epub 2021 Mar 17.

Key Laboratory of Experimental Teratology, Ministry of Education, Department of Cell Biology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.

Aberrant expression of splicing factors was found to promote tumorigenesis and the development of human malignant tumors. Nevertheless, the underlying mechanisms and functional relevance remain elusive. We here show that USP39, a component of the spliceosome, is frequently overexpressed in high-grade serous ovarian carcinoma (HGSOC) and that an elevated level of USP39 is associated with a poor prognosis. USP39 promotes proliferation/invasion in vitro and tumor growth in vivo. Importantly, USP39 was transcriptionally activated by the oncogene protein c-MYC in ovarian cancer cells. We further demonstrated that USP39 colocalizes with spliceosome components in nuclear speckles. Transcriptomic analysis revealed that USP39 deletion led to globally impaired splicing that is characterized by skipped exons and overrepresentation of introns and intergenic regions. Furthermore, RNA immunoprecipitation sequencing showed that USP39 preferentially binds to exon-intron regions near 5' and 3' splicing sites. In particular, USP39 facilitates efficient splicing of HMGA2 and thereby increases the malignancy of ovarian cancer cells. Taken together, our results indicate that USP39 functions as an oncogenic splicing factor in ovarian cancer and represents a potential target for ovarian cancer therapy.
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http://dx.doi.org/10.1038/s41419-021-03581-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969951PMC
March 2021

CDCA8, targeted by MYBL2, promotes malignant progression and olaparib insensitivity in ovarian cancer.

Am J Cancer Res 2021 1;11(2):389-415. Epub 2021 Feb 1.

Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University Jinan 250012, China.

Ovarian cancer is the most lethal gynecologic malignancy. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective in treating ovarian cancer. However, cancer cell insensitivity and resistance remain challenges. Determination of the exact chemoresistance mechanisms and potential targeted therapies is urgent. CDCA8 (cell division cycle associated 8) participates in the tumorigenesis of various cancers; however, the exact biological function of CDCA8 in ovarian cancer remains obscure. Here, we found that CDCA8 was overexpressed in ovarian cancer and that high expression of CDCA8 promoted the proliferation of ovarian cancer cells in vitro and in vivo. Moreover, silencing of CDCA8 sensitized ovarian cancer cells to olaparib and cisplatin by inducing G2/M arrest, accelerating apoptosis, increasing DNA damage and interfering with RAD51 accumulation in vitro. In addition, MYBL2 (MYB proto-oncogene-like 2), identified as an upstream transcription factor of CDCA8, was positively correlated with the expression level of CDCA8 in ovarian cancer. Finally, MYBL2 enhanced the aggressive characteristics of ovarian cancer cells by regulating CDCA8. In conclusion, high CDCA8 expression was involved in the tumorigenesis, aggressiveness and chemoresistance of ovarian cancer. CDCA8 silencing combined with olaparib treatment might lead to substantial progress in ovarian cancer targeted therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868764PMC
February 2021

Olaparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 mutation: SOLO1 China cohort.

Gynecol Oncol 2021 01 27;160(1):175-181. Epub 2020 Nov 27.

AstraZeneca, Shanghai, China.

Purpose: Maintenance therapy with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib provided a substantial progression-free survival (PFS) benefit compared with placebo in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (BRCAm) who were in clinical complete or partial response following platinum-based chemotherapy in the Phase III SOLO1 global study. This led to the approval of maintenance olaparib in China, USA, EU, Japan and other countries, in the newly diagnosed setting. This separate China cohort of the SOLO1 study investigated the efficacy and safety of maintenance olaparib within the Chinese population.

Patients And Methods: In this double-blind, multicentre study, patients were randomized 2:1 to receive oral olaparib tablets (300 mg twice daily) or placebo. The primary endpoint was investigator-assessed PFS (modified RECIST v1.1).

Results: Of the 64 randomized patients, 44 received olaparib and 20 placebo. Olaparib reduced the risk of disease progression or death by 54% compared with placebo (HR 0.46, 95% Cl 0.23-0.97; median PFS was not reached in the olaparib arm vs 9.3 months in the placebo arm). The most common AEs in the olaparib arm were nausea (63.6 vs 25.0% with placebo), anaemia (59.1 vs 15.0%) and leukopenia (54.5 vs 20.0%). Grade ≥3 AEs were experienced by 56.8% of olaparib patients and 30.0% of placebo patients.

Conclusions: Results in the SOLO1 China cohort support the use of olaparib as maintenance treatment for Chinese patients with newly diagnosed advanced ovarian cancer who have a BRCAm and are in complete or partial response after platinum-based chemotherapy.
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http://dx.doi.org/10.1016/j.ygyno.2020.10.005DOI Listing
January 2021

PBK promotes aggressive phenotypes of cervical cancer through ERK/c-Myc signaling pathway.

J Cell Physiol 2021 Apr 13;236(4):2767-2781. Epub 2020 Nov 13.

Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.

Cervical cancer is the fourth most frequent cancer in women worldwide. PDZ-binding kinase (PBK) is proven to promote the malignant behaviors of various carcinomas. However, its functional roles and oncogenic mechanisms in cervical cancer are poorly understood. In this study, we reported that PBK was highly expressed in cervical cancer tissues. PBK promoted the proliferation, metastasis, and cisplatin resistance of cervical cancer cells. OTS514, a specific PBK inhibitor, could significantly suppress proliferation and metastasis of cervical cancer cells in vitro and in a xenograft model. Besides, OTS514 could enhance cisplatin-based chemosensitivity in cervical cancer cells. Mechanistically, PBK promoted the expression and stabilization of c-Myc through phosphorylating ERK1/2. OTS514 suppressed the phosphorylation of ERK1/2 and the transcriptional activity of c-Myc. Furthermore, inhibition of the ERK signal pathway by U0126 reversed the increased proliferation and metastasis induced by overexpression of PBK. Exogenous expression of c-Myc counteracted the decreased proliferation and metastasis evoked by knockdown of PBK. In conclusion, PBK promoted the malignant progression of cervical cancer through ERK/c-Myc signal pathway. PBK might be a promising molecular target for cervical cancer treatment.
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http://dx.doi.org/10.1002/jcp.30134DOI Listing
April 2021

RECQL4, Negatively Regulated by miR-10a-5p, Facilitates Cell Proliferation and Invasion via MAFB in Ovarian Cancer.

Front Oncol 2020 4;10:524128. Epub 2020 Sep 4.

Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

The high frequency of somatic copy number alterations, as opposed to point mutations, is considered a unique feature of ovarian cancer. Amplification-dependent overexpression of RecQ protein-like 4 (RECQL4), which participates in DNA replication and repair, mediates the development of various cancers, but its pathobiological and clinical roles are poorly understood. Here, using bioinformatics analysis, RECQL4 amplification was found to occur in 27% of ovarian cancer samples in the TCGA cohort. RECQL4 was found to be upregulated and associated with a poor prognosis based on the immunohistochemistry staining of ovarian cancer. Functionally, RECQL4 overexpression increased proliferation and invasion of ovarian cancer cells. RECQL4 silencing had the opposite effects. In addition, RECQL4 knockdown enhanced the sensitivity of ovarian cancer cells to cisplatin and PARP inhibitor (PARPi). Further mechanistic investigations revealed that MAFB was a downstream target of RECQL4. The oncogenic effect of RECQL4 was attenuated after MAFB knockdown. Moreover, RECQL4 overexpression was negatively regulated by the tumor suppressor miR-10a-5p. Collectively, these findings indicate that genomic amplification and low expression of miR-10a-5p contribute to RECQL4 overexpression in ovarian cancer. This is the first study to reveal the oncogenic functions and clinical significance of RECQL4 in ovarian cancer.
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http://dx.doi.org/10.3389/fonc.2020.524128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500455PMC
September 2020

Identification of lncRNA Signature Associated With Pan-Cancer Prognosis.

IEEE J Biomed Health Inform 2021 Jun 3;25(6):2317-2328. Epub 2021 Jun 3.

Long noncoding RNAs (lncRNAs) have emerged as potential prognostic markers in various human cancers as they participate in many malignant behaviors. However, the value of lncRNAs as prognostic markers among diverse human cancers is still under investigation, and a systematic signature based on these transcripts that related to pan-cancer prognosis has yet to be reported. In this study, we proposed a framework to incorporate statistical power, biological rationale, and machine learning models for pan-cancer prognosis analysis. The framework identified a 5-lncRNA signature (ENSG00000206567, PCAT29, ENSG00000257989, LOC388282, and LINC00339) from TCGA training studies (n = 1,878). The identified lncRNAs are significantly associated (all P ≤ 1.48E-11) with overall survival (OS) of the TCGA cohort (n = 4,231). The signature stratified the cohort into low- and high-risk groups with significantly distinct survival outcomes (median OS of 9.84 years versus 4.37 years, log-rank P = 1.48E-38) and achieved a time-dependent ROC/AUC of 0.66 at 5 years. After routine clinical factors involved, the signature demonstrated better performance for long-term prognostic estimation (AUC of 0.72). Moreover, the signature was further evaluated on two independent external cohorts (TARGET, n = 1,122; CPTAC, n = 391; National Cancer Institute) which yielded similar prognostic values (AUC of 0.60 and 0.75; log-rank P = 8.6E-09 and P = 2.7E-06). An indexing system was developed to map the 5-lncRNA signature to prognoses of pan-cancer patients. In silico functional analysis indicated that the lncRNAs are associated with common biological processes driving human cancers. The five lncRNAs, especially ENSG00000206567, ENSG00000257989 and LOC388282 that never reported before, may serve as viable molecular targets common among diverse cancers.
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http://dx.doi.org/10.1109/JBHI.2020.3027680DOI Listing
June 2021

Sentinel lymph node biopsy versus pelvic lymphadenectomy in early-stage cervical cancer: a multi-center randomized trial (PHENIX/CSEM 010).

Int J Gynecol Cancer 2020 11 24;30(11):1829-1833. Epub 2020 Sep 24.

Department of Gynecologic Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

Background: There is no accepted strategy for applying sentinel lymph node (SLN) biopsy as an alternative to pelvic lymphadenectomy in cervical cancer. It is unclear whether and when pelvic lymphadenectomy can be safely replaced by SLN biopsy alone.

Primary Objective: To comprehensively compare the oncological outcomes of SLN biopsy with pelvic lymphadenectomy in patients with and without SLN metastasis.

Study Hypothesis: It is hypothesized that the oncological outcomes provided by SLN biopsy are non-inferior to those of pelvic lymphadenectomy in patients with clinically early-stage cervical cancer if risk-adapted adjuvant treatments are given.

Trial Design: All eligible patients will undergo SLN biopsy at the start of surgery. The resected SLNs will be submitted for frozen section examination. and patients will be triaged into the PHENIX-I (SLN-negative) or PHENIX-II (SLN-positive) cohort. In each cohort of this trial, patients will be randomized in a 1:1 ratio into the experimental (SLN biopsy alone) or reference (pelvic lymphadenectomy) arm. Radical hysterectomy will be performed for all patients, and adjuvant treatments will be planned according to post-operative pathological factors.

Major Inclusion/exclusion Criteria: Patients aged between 18 and 65 years with histologically confirmed, untreated stage IA1 (lymphovascular space involvement), IA2, IB1, and IB2 cervical squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma.

Primary Endpoint: The primary endpoint is disease-free survival.

Sample Size: Estimated sample sizes of 830 and 250 are required to fulfill the study objectives of PHENIX-I and II, respectively.

Estimated Dates For Completing Accrual And Presenting Results: As of May 2020, more than 600 eligible patients have been enrolled. Enrollment is expected to be completed by December 2022, and presentation of results is expected in 2026.

Trial Registration: NCT02642471.
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http://dx.doi.org/10.1136/ijgc-2020-001857DOI Listing
November 2020

FBLN5 is targeted by microRNA‑27a‑3p and suppresses tumorigenesis and progression in high‑grade serous ovarian carcinoma.

Oncol Rep 2020 Nov 3;44(5):2143-2151. Epub 2020 Sep 3.

Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.

High-grade serous ovarian carcinoma (HGSOC) is one of the most lethal gynecological malignancies; however, the precise molecular mechanisms have not been fully characterized. Fibulin‑5 (FBLN‑5) is an extracellular matrix (ECM) glycoprotein, and plays a crucial role in maintaining the stability of ECM structures, regulating cell proliferation and tumorigenesis. In the present study, the expression of FBLN‑5, as determined by western blot analysis and immunohistochemistry, was significantly increased in normal fallopian tube (FT) samples compared with that in HGSOC samples, and decreased FBLN5 expression was associated with unfavorable prognosis of HGSOC. Functional characterization revealed that FBLN5 overexpression significantly inhibited migration, invasion and proliferation abilities of ovarian cancer cells in vitro. Furthermore, micro (mi)RNA‑27a‑3p (miR‑27a‑3p) was revealed to be increased in HGSOC, and dual‑luciferase reporter assay indicated that miR‑27a‑3p was functioned as a negative regulator of FBLN5 by directly binding with its 3'‑untranslated region. Collectively, FBLN5 expression was associated with prognosis, proliferation, and metastasis in HGSOC. We hypothesized that FBLN5 was targeted by miR‑27a‑3p and may serve as a biomarker and provide a new therapeutic approach for the treatment of HGSOC.
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http://dx.doi.org/10.3892/or.2020.7749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550983PMC
November 2020

Prognostic Assessment of Cervical Cancer Patients by Clinical Staging and Surgical-Pathological Factor: A Support Vector Machine-Based Approach.

Front Oncol 2020 5;10:1353. Epub 2020 Aug 5.

Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

The International Federation of Gynecology and Obstetrics (FIGO) staging system is considered the most powerful prognostic factor in patients with cervical cancer. In addition, other surgical-pathological risk factors have been demonstrated to have significance in predicting the prognosis of patients. Therefore, the purpose of this study was to investigate the effects of the FIGO staging system and surgical-pathological risk factors on the prognosis of cervical cancer patients. A retrospective study was performed on patients diagnosed with cervical cancer at FIGO stage IB1-IIA2. Kaplan-Meier, Cox proportional hazards regression analysis and the support vector machine (SVM) algorithm were used to assess and validate the high-risk factors related to recurrence and death. A total of 647 patients were included. Kaplan-Meier analysis showed that five high-risk factors, including FIGO stage, status of pelvic lymph node, parametrial involvement, tumor size, and depth of cervical cancer, had a significant effect on the prognosis of patients. In multivariate analysis, pelvic lymph node metastasis (hazard ratio [HR] 2.415, 95% confidence interval [CI] 1.471-3.965), parametrial involvement (HR 2.740, 95% CI 1.092-6.872) and >2/3 depth of cervical invasion (HR 2.263, 95% CI 1.045-4.902) were three independent risk factors of disease-free survival. Pelvic lymph node metastasis (HR 3.855, 95% CI 2.125-6.991) and parametrial involvement (HR 3.871, 95% CI 1.375-10.900) were two independent risk factors for overall survival. When all five high-risk factors were assembled and used for classification prediction through SVM, it achieved the highest prediction accuracy of recurrence (accuracy = 69.1%). The highest prediction accuracy for survival was 94.3% when only using the two independent predictors (the pathological status of lymph nodes and parametrium involvement) by SVM classifiers. Among the 13 groups of intermediate-risk factor, the combination of tumor size, histology and grade of differentiation was more accurate in predicting prognosis than the intermediate-risk factors in the Sedlis criteria (recurrence: 86.8% vs. 60.0%; death: 92.0% vs. 71.6%). The combination of FIGO stage and surgical-pathological risk factors can further enhance the prediction accuracy of the prognosis in patients with early-stage cervical cancer. Histology and grade of differentiation can further improve the prediction accuracy of intermediate-risk factors in the Sedlis criteria.
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http://dx.doi.org/10.3389/fonc.2020.01353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419674PMC
August 2020

Cyclin F and KIF20A, FOXM1 target genes, increase proliferation and invasion of ovarian cancer cells.

Exp Cell Res 2020 10 7;395(2):112212. Epub 2020 Aug 7.

Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China. Electronic address:

Increased expression of FOXM1 is observed in a variety of human malignancies. The downstream target genes of FOXM1 involved in tumorigenesis and development are not fully elucidated in ovarian cancer. Here, we identified Cyclin F, a substrate recognition subunit of SCF (Skp1-Cul1-F-box protein) complex, and Kinesin Family Member 20A (KIF20A) were transcriptionally regulated by FOXM1 in ovarian cancer. Accordingly, Cyclin F and KIF20A were commonly overexpressed in ovarian cancer. Functionally, forced expression of Cyclin F or KIF20A significantly enhanced while knockdown of them decreased proliferation and invasion of ovarian cancer cells. Importantly, high levels of Cyclin F and KIF20A correlated with poor prognosis in patients with ovarian cancer. Our findings indicate that Cyclin F and KIF20A are functional targets of FOXM1 which might be potential drug targets in ovarian cancer.
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http://dx.doi.org/10.1016/j.yexcr.2020.112212DOI Listing
October 2020

promotes cancer proliferation and metastasis in high-grade serous ovarian cancer.

Oncol Lett 2020 Aug 21;20(2):1179-1192. Epub 2020 May 21.

Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.

Ovarian cancer is a type of gynecological cancer with the highest mortality rate worldwide. Due to a lack of effective screening methods, most cases are diagnosed at later stages where the survival rates are poor. Thus, it is termed a 'silent killer' and is the most lethal of all the malignancies in women. IQ motif containing GTPase Activating Protein 3 () is a member of the Rho family of GTPases, and plays a crucial role in the development and progression of several types of cancer. The aim of the present study was to investigate the oncogenic functions and mechanisms of on the proliferation and metastasis of high-grade serous ovarian cancer (HGSOC). Therefore, the expression levels of in HGSOC and normal tissue samples were compared, and knockdown was performed to examine its functional role using various and experiments. It was demonstrated that the expression of was upregulated in HGSOC tissues compared with the healthy tissues; this differential expression was also observed in the ovarian cancer cell lines. Functional experimental results suggested that silencing significantly reduced proliferation, migration and invasion in ovarian cancer cell lines. Moreover, experimental findings validated the results, where the tumorigenic and metastatic capacities of -silenced cells were significantly lower in the nude mice compared with the mice implanted with the control cells. Furthermore, knockdown of resulted in increased apoptosis, and the effects of expression on various epithelial-mesenchymal transition markers were identified, suggesting a possible mechanism associated with the role of in metastasis. The effect of silencing on chemosensitivity towards olaparib was also assessed. Collectively, the present results indicated that is a potential diagnostic and prognostic marker, and a putative therapeutic target of HGSOC.
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http://dx.doi.org/10.3892/ol.2020.11664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377165PMC
August 2020

Predicting the Risk of Adverse Events in Pregnant Women With Congenital Heart Disease.

J Am Heart Assoc 2020 07 14;9(14):e016371. Epub 2020 Jul 14.

Department of Obstetrics and Gynecology Qilu Hospital Cheeloo College of Medicine Shandong University Jinan Shandong China.

Background Women with congenital heart disease are considered at high risk for adverse events. Therefore, we aim to establish 2 prediction models for mothers and their offspring, which can predict the risk of adverse events occurred in pregnant women with congenital heart disease. Methods and Results A total of 318 pregnant women with congenital heart disease were included; 213 women were divided into the development cohort, and 105 women were divided into the validation cohort. Least absolute shrinkage and selection operator was used for predictor selection. After validation, multivariate logistic regression analysis was used to develop the model. Machine learning algorithms (support vector machine, random forest, AdaBoost, decision tree, k-nearest neighbor, naïve Bayes, and multilayer perceptron) were used to further verify the predictive ability of the model. Forty-one (12.9%) women experienced adverse maternal events, and 93 (29.2%) neonates experienced adverse neonatal events. Seven high-risk factors were discovered in the maternal model, including New York Heart Association class, Eisenmenger syndrome, pulmonary hypertension, left ventricular ejection fraction, sinus tachycardia, arterial blood oxygen saturation, and pregnancy duration. The machine learning-based algorithms showed that the maternal model had an accuracy of 0.76 to 0.86 (area under the receiver operating characteristic curve=0.74-0.87) in the development cohort, and 0.72 to 0.86 (area under the receiver operating characteristic curve=0.68-0.80) in the validation cohort. Three high-risk factors were discovered in the neonatal model, including Eisenmenger syndrome, preeclampsia, and arterial blood oxygen saturation. The machine learning-based algorithms showed that the neonatal model had an accuracy of 0.75 to 0.80 (area under the receiver operating characteristic curve=0.71-0.77) in the development cohort, and 0.72 to 0.79 (area under the receiver operating characteristic curve=0.69-0.76) in the validation cohort. Conclusions Two prenatal risk assessment models for both adverse maternal and neonatal events were established, which might assist clinicians in tailoring precise management and therapy in pregnant women with congenital heart disease.
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http://dx.doi.org/10.1161/JAHA.120.016371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660735PMC
July 2020

Mitochondrial superoxide contributes to oxidative stress exacerbated by DNA damage response in RAD51-depleted ovarian cancer cells.

Redox Biol 2020 09 8;36:101604. Epub 2020 Jun 8.

State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, 215123, China. Electronic address:

Ovarian cancer is the most lethal gynecological malignancy. Abnormal homologous recombination repair, high level of reactive oxygen species (ROS) and upregulation of antioxidant genes are characteristic features of ovarian cancer. However, the molecular mechanisms governing the redox homeostasis in ovarian cancer cells remain to be fully elucidated. We here demonstrated a critical role of RAD51, a protein essential for homologous recombination, in the maintenance of redox homeostasis. We found that RAD51 is overexpressed in high grade serous ovarian cancer and is associated with poor prognosis. Depletion or inhibition of RAD51 results in G2/M arrest, increased production of reactive oxygen species and accumulation of oxidative DNA damage. Importantly, antioxidant N-acetylcysteine (NAC) significantly attenuated the induction of DNA damage and the perturbation of proliferation caused by RAD51 depletion. We further demonstrated that RAD51 inhibition or depletion led to elevated production of mitochondrial superoxide and increased accumulation of mitochondria. Moreover, CHK1 activation is required for the G2/M arrest and the generation of mitochondrial stress in response to RAD51 depletion. Together, our results indicate that nuclear DNA damage caused by RAD51 depletion may trigger mitochondria-originated redox dysregulation. Our findings suggest that a vicious cycle of nuclear DNA damage, mitochondrial accumulation and oxidative stress may contribute to the tumor-suppressive effects of RAD51 depletion or inhibition.
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http://dx.doi.org/10.1016/j.redox.2020.101604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303666PMC
September 2020

Management of gynecology patients during the coronavirus disease 2019 pandemic: Chinese expert consensus.

Am J Obstet Gynecol 2020 07 15;223(1):3-8. Epub 2020 May 15.

Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China. Electronic address:

Since December 2019, the outbreak of novel coronavirus disease 2019 became a major epidemic threat in China and later spread worldwide. During the coronavirus disease 2019 outbreak in mainland China, the Chinese Obstetricians and Gynecologists Association distributed guidelines regarding the care of gynecologic patients. These guidelines were developed by the Department of Obstetrics and Gynecology at the Peking Union Medical College Hospital and represent an effort to integrate infection control strategy and promote professionalism in medical practice. The guidelines represent collaboration with experts from 31 provinces and autonomous regions of mainland China over 2 weeks' time. With the implementation of these guidelines, no nosocomial infections of coronavirus disease 2019 have been identified at the Peking Union Medical College Hospital. We think these guidelines might be helpful to departments of obstetrics and gynecology internationally during these unprecedented times. In our guidelines, we describe basic infection precaution principles, an epidemiologic screening tool, prioritization of surgical procedures, and operating room requirements. Using these principles, we then review the management of gynecologic patients during the coronavirus disease 2019 epidemic in the outpatient and operative and nonoperative inpatient settings and in clinical trials.
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http://dx.doi.org/10.1016/j.ajog.2020.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228711PMC
July 2020

NAC1 attenuates BCL6 negative autoregulation and functions as a BCL6 coactivator of FOXQ1 transcription in cancer cells.

Aging (Albany NY) 2020 05 14;12(10):9275-9291. Epub 2020 May 14.

Department of Toxicology and Cancer Biology, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.

Background: Nucleus accumbens-associated protein 1 (NAC1) has multifaceted roles in cancer pathogenesis and progression, including the development of drug resistance, promotion of cytokinesis, and maintenance of "stem cell-like" phenotypes. NAC1 is a transcriptional co-regulator belonging to the bric-a-brac tramtrack broad (BTB) family of proteins, although it lacks the characteristic DNA binding motif of the BTB family. The formation of higher-order transcription complexes likely depends on its interaction with other DNA-binding co-factors.

Results: NAC1 interacts with BCL6 via its C-terminal BEN domain and forms a complex that binds the promoter region and activates transcription of the NAC1 target gene, FOXQ1. NAC1 and BCL6 were coordinately upregulated. Our analysis also identified a novel function of NAC1 in attenuating BCL6 auto-downregulation in ovarian cancer. Lastly, we found a significant overlap among NAC1- and BCL6-regulated genes in tumor cells, suggesting that NAC1 and BCL6 coordinately control transcription in cancer.

Conclusions: The results of this study provide a novel mechanistic insight into the oncogenic roles of NAC1 and underline the importance of developing the NAC1/BCL6-targeted cancer therapy.

Methods: Using the Cistrome database and Chromatin Immunoprecipitation (ChIP) analyses, we identified BCL6 as a potential NAC1- interacting molecule. Co-immunoprecipitation (Co-IP), luciferase reporter assay, immunohistochemistry and microarray analysis were performed to analyze the interaction between NAC1 and BCL6 and the mechanisms by which they regulate the downstream genes including FOXQ1.
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http://dx.doi.org/10.18632/aging.103203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288929PMC
May 2020

Analysis of the association between the XRCC2 rs3218536 polymorphism and ovarian cancer risk.

Arch Med Sci 2020 25;16(3):682-691. Epub 2020 Apr 25.

Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China.

Introduction: Results conflict on the association between the XRCC2 rs3218536 polymorphism and ovarian cancer risk, despite wide-ranging investigations. This meta-analysis examines whether the XRCC2 rs3218536 polymorphism is associated with ovarian cancer risk.

Material And Methods: Eligible case-control studies were searched in PubMed. We therefore performed a meta-analysis of 5,802 ovarian cancer cases and 9,390 controls from 7 articles published. The strength of association between XRCC2 rs3218536 polymorphism and ovarian cancer susceptibility was calculated using pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs).

Results: No statistically significant associations between XRCC2 rs3218536 polymorphism and ovarian cancer risk were found in any genetic models. However, a significant relationship with ovarian cancer risk was discovered when the high quality studies were pooled in the meta-analysis (AA vs. GG: OR = 0.59, 95% CI: 0.37-0.94, = 0.03; GA vs. GG: OR = 0.87, 95% CI: 0.78-0.96, = 0.009; GA + AA vs. GG: OR = 0.85, 95% CI: 0.77-0.94, = 0.003; AA vs. GG + GA: OR = 0.60, 95% CI: 0.38-0.95, = 0.03).

Conclusions: This meta-analysis shows that the XRCC2 rs3218536 polymorphism was associated with ovarian cancer risk overall for high quality studies. Non-Caucasian groups and high quality studies should be further studied.
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http://dx.doi.org/10.5114/aoms.2020.94657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212224PMC
April 2020

Upregulated MELK Leads to Doxorubicin Chemoresistance and M2 Macrophage Polarization via the miR-34a/JAK2/STAT3 Pathway in Uterine Leiomyosarcoma.

Front Oncol 2020 22;10:453. Epub 2020 Apr 22.

Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Ji'nan, China.

Uterine leiomyosarcoma (ULMS) is the most lethal gynecologic malignancy with few therapeutic options. Chemoresistance prevails as a major hurdle in treating this malignancy, yet the mechanism of chemoresistance remains largely unclear. In this study, we certified MELK as a poor prognostic marker through bioinformatic analysis of the GEO database. Cellular experiments revealed that MELK played an essential role in ULMS cells' chemoresistance and that a high expression of MELK could lead to doxorubicin resistance. mRNA profiling uncovered the pathways that MELK was involved in which led to doxorubicin resistance. MELK was found to affect ULMS cells' chemoresistance through an anti-apoptotic mechanism via the JAK2/STAT3 pathway. miRNA profiling also revealed that upregulated MELK could induce the decrease of miRNA-34a (regulated by JAK2/STAT3 pathway). We detected that MELK overexpression could induce M2 macrophage polarization via the miR-34a/JAK2/STAT3 pathway, contributing to doxorubicin chemoresistance in the tumor microenvironment. OTSSP167, a MELK inhibitor, may increase ULMS sensitivity to doxorubicin. Our investigation could propose novel targets for early diagnosis and precision therapy in ULMS patients.
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http://dx.doi.org/10.3389/fonc.2020.00453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188922PMC
April 2020

Development and Validation of a Deep Learning Radiomics Model Predicting Lymph Node Status in Operable Cervical Cancer.

Front Oncol 2020 15;10:464. Epub 2020 Apr 15.

Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.

To develop and validate a deep learning radiomics model, which could predict the lymph node metastases preoperatively in cervical cancer patients. We included a cohort of 226 pathological proven operable cervical cancer patients in two academic medical institutions from December 2014 to November 2017. Then this dataset was split into training set ( = 176) and independent testing set ( = 50) randomly. Five radiomic features were selected and a radiomic signature was established. We then combined these five radiomic features with the preoperative tumor histology and grade of these patients together. Baseline logistic regression model (LRM) and support vector machine model (SVM) were established for the comparison. We then explored the performance of a deep neural network (DNN), which is a popular deep learning model nowadays. Finally, performance of this DNN was validated in another independent test set including 50 cases of operable cervical cancer patients. One thousand forty-five radiomic features were extracted for each patient. Twenty-eight features were found to be significantly correlated with the lymph node status in these patients ( < 0.05). Five radiomic features were further selected for further study due to their higher predictive powers. Baseline LRM incorporating these five radiomic and two clinicopathological features was established, which had an area under receiver operating characteristic curve (ROC) of 0.7372 and an accuracy of 89.20%. The established DNN model had four neural layers, in which layer there were 10 neurons. Adagrad optimizer and 1,500 iterations were used in training. The trained DNN had an area under curve (AUC) of 0.99 and an accuracy of 97.16% in the internal validation. To exclude the overfitting, independent external validation was also performed. AUC and accuracy in test set could still retain 0.90 and 92.00% respectively. This study used deep learning method to provide a comprehensive predictive model using preoperative CT images, tumor histology, and grade in cervical cancer patients. This model showed an acceptable accuracy in the prediction of lymph node status in cervical cancer. Our model may help identifying those patients who could benefit a lot from radiation therapy rather than primary hysterectomy surgery if this model could resist strict testing of future randomized controlled trials (RCTs).
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http://dx.doi.org/10.3389/fonc.2020.00464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179686PMC
April 2020

Correction to: Kallistatin inhibits tumour progression and platinum resistance in high-grade serous ovarian cancer.

J Ovarian Res 2020 03 13;13(1):28. Epub 2020 Mar 13.

Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Ji'nan, Shandong, 250012, People's Republic of China.

The original article [1] contains errors in Fig. 3C, Results and Discussion.
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http://dx.doi.org/10.1186/s13048-020-00628-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071567PMC
March 2020

MYC-regulated pseudogene HMGA1P6 promotes ovarian cancer malignancy via augmenting the oncogenic HMGA1/2.

Cell Death Dis 2020 03 3;11(3):167. Epub 2020 Mar 3.

Key Laboratory of Experimental Teratology, Ministry of Education, Department of Cell Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, 250012, Jinan, Shandong Province, China.

Pseudogenes have long been considered as nonfunctional genomic sequences. Recent studies have shown that they can potentially regulate the expression of protein-coding genes and are dysregulated in diseases including cancer. However, the potential roles of pseudogenes in ovarian cancer have not been well studied. Here we characterized the pseudogene expression profile in HGSOC (high-grade serous ovarian carcinoma) by microarray. We identified 577 dysregulated pseudogenes and most of them were up-regulated (538 of 577). HMGA1P6 (High mobility group AT-hook 1 pseudogene 6) was one of the overexpressed pseudogenes and its expression was inversely correlated with patient survival. Mechanistically, HMGA1P6 promoted ovarian cancer cell malignancy by acting as a ceRNA (competitive endogenous RNA) that led to enhanced HMGA1 and HMGA2 expression. Importantly, HMGA1P6 was transcriptionally activated by oncogene MYC in ovarian cancer. Our findings reveal that MYC may contribute to oncogenesis through transcriptional regulation of pseudogene HMGA1P6 in ovarian cancer.
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http://dx.doi.org/10.1038/s41419-020-2356-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054391PMC
March 2020

MiR-509-3 augments the synthetic lethality of PARPi by regulating HR repair in PDX model of HGSOC.

J Hematol Oncol 2020 01 31;13(1). Epub 2020 Jan 31.

Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, Shandong, 250012, People's Republic of China.

Background: PARP inhibitors have been the most promising target drugs with widely proven benefits among ovarian cancer patients. Although platinum-response, HR-related genes, or HRD genomic scar detection are acceptably used in assessment of Olaparib response, there are still evident limitations in the present approaches. Therefore, we aim to investigate more accurate approaches to predict Olaparib sensitivity and effective synergistic treatment strategies.

Methods: We probed two databases (TCGA and Qilu Hospital) in order to quest novel miRNAs associated with platinum-sensitivity or HR-related genes. Cellular experiments in vitro or in vivo and PDX models were utilized to validate their role in tumor suppression and Olaparib sensitizing. Furthermore, HR gene mutation was analyzed through WES to explore the relation between HR gene mutation and Olaparib response.

Results: High miR-509-3 expression indicated better response to platinum and longer progression-free and overall survival in two independent ovarian cancer patient cohorts (high vs. low miR-509-3 expression; PFS: TCGA P < 0.05, Qilu P < 0.05; OS: TCGA P < 0.05, Qilu P < 0.01). MiR-509-3 could impair the proliferation, migration, and invasion ability but enhance the sensitivity to Olaparib of ovarian cancer cell in vitro and in vivo by directly targeting HMGA2 and RAD51. In two PDX cases (PDX1 and PDX9), miR-509-3 could significantly increase the sensitivity to Olaparib along with the decrease of RAD51 positive rate (mean tumor weight NC + Olaparib vs. miR-509 + Olaparib; PDX1 P < 0.05, PDX9 P < 0.05). Additionally, in PDX8, miR-509-3 treatment dramatically reversed the Olaparib insensitivity (P < 0.05) by downregulating RAD51 expression. RAD51 functional detection revealed that all Olaparib sensitive cases exhibited low RAD51 positive rate (lesser than 50%) in treated groups. Furthermore, among the four HR gene mutation patients, three harbored HR core gene mutation and were sensitive to Olaparib while the remaining one with non-HR core gene mutation did not respond well to Olaparib.

Conclusions: MiR-509-3 can sensitize ovarian cancer cells to Olaparib by impeding HR, which makes it a potential target in PARPi synergistic treatment. HR core gene analysis and RAD51 functional detection are prospectively feasible in prediction of PARPi response.
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http://dx.doi.org/10.1186/s13045-020-0844-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995078PMC
January 2020

Overexpression of PRC1 indicates a poor prognosis in ovarian cancer.

Int J Oncol 2020 Mar 10;56(3):685-696. Epub 2020 Jan 10.

Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.

Protein regulator of cytokinesis‑1 (PRC1) is a microtubule‑associated factor involved in cytokinesis. Recent studies have indicated that PRC1 overexpression is involved in tumorigenesis in multiple types of human cancer. However, the expression, biological functions and the prognostic significance of PRC1 in ovarian cancer have not yet been clarified. In this study, it was confirmed that the PRC1 mRNA and protein expression levels were upregulated in high‑grade serous ovarian carcinoma (HGSOC) tissues, particularly in patients without breast cancer susceptibility gene (BRCA) pathogenic mutations. PRC1 overexpression contributed to drug resistance, tumor recurrence and a poor prognosis. The findings also indicated that PRC1 knockdown decreased the proliferation, metastasis and multidrug resistance of ovarian cancer cells in vitro. It was also demonstrated that forkhead box protein M1 (FOXM1) regulated the mRNA and protein expression of PRC1. Dual‑luciferase reporter assay and rescue assay confirmed that PRC1 was a direct crucial downstream target of FOXM1. On the whole, the findings of this study confirmed that PRC1 was a major prognostic factor of HGSOC and a promising therapeutic biomarker for the treatment of ovarian cancer.
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http://dx.doi.org/10.3892/ijo.2020.4959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010224PMC
March 2020

Kallistatin inhibits tumour progression and platinum resistance in high-grade serous ovarian cancer.

J Ovarian Res 2019 Dec 29;12(1):125. Epub 2019 Dec 29.

Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Ji'nan, Shandong, 250012, People's Republic of China.

Ovarian cancer is the most lethal gynaecologic malignancy. Although there are various subtypes of ovarian cancer, high-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer deaths. Chemoresistance is the primary reason for the unfavourable prognosis of HGSOC. Kallistatin (KAL), also known as SERPINA4, is part of the serpin family. Kallistatin has been discovered to exert multiple effects on angiogenesis, inflammation and tumour progression. However, the roles and clinical significance of kallistatin in HGSOC remain unclear. Here, we showed that kallistatin was significantly downregulated in HGSOC compared to normal fallopian tube (FT) tissues. Low expression of kallistatin was associated with unfavourable prognosis and platinum resistance in HGSOC. Overexpression of kallistatin significantly inhibited proliferation and metastasis, and enhanced platinum sensitivity and apoptosis in ovarian cancer cells. Collectively, these findings demonstrate that kallistatin serves as a prognostic predictor and provide a potential therapeutic target for HGSOC.
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http://dx.doi.org/10.1186/s13048-019-0601-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935502PMC
December 2019

Evaluation of COC183B2 antibody targeting ovarian cancer by near-infrared fluorescence imaging.

Chin J Cancer Res 2019 Aug;31(4):673-685

Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China.

Objective: To evaluate the imaging potential of a novel near-infrared (NIR) probe conjugated to COC183B2 monoclonal antibodies (MAb) in ovarian cancer (OC).

Methods: The expression of OC183B2 antigen in OC was determined by immunohistochemical (IHC) staining using tissue microarrays with the H-score system and immunofluorescence (IF) staining of tumor cell lines. Imaging probes with the NIR fluorescent dye cyanine 7 (Cy7) conjugated to COC183B2 Mab were chemically engineered. OC183B2-positive human OC cells (SKOV3-Luc) were injected subcutaneously into BALB/c nude mice. Bioluminescent imaging (BLI) was performed to detect tumor location and growth. COC183B2-Cy7 at 1.1, 3.3, 10, or 30 μg were used for fluorescence imaging, and phosphate-buffered saline (PBS), free Cy7 dye and mouse isotype immunoglobulin G (IgG)-Cy7 (delivered at the same doses as COC183B2-Cy7) were used as controls.

Results: The expression of OC183B2 with a high H-score was more prevalent in OC tissue than fallopian tube (FT) tissue. Among 417 OC patients, the expression of OC183B2 was significantly correlated with the histological subtype, histological grade, residual tumor size, relapse state and survival status. IF staining demonstrated that COC183B2 specifically expressed in SKOV3 cells but not HeLa cells. NIR fluorescence imaging indicated that COC183B2-Cy7 was mainly distributed in the xenograft and liver with optimal tumor-to-background (T/B) ratios in the xenograft at 30 μg dose. The highest fluorescent signals in the tumor were observed at 96 h post-injection (hpi). fluorescence imaging revealed the fluorescent signals mainly from the tumor and liver. IHC analysis confirmed that xenografts were OC183B2 positive.

Conclusions: COC183B2 is a good candidate for NIR fluorescence imaging and imaging-guided surgery in OC.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2019.04.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736662PMC
August 2019

Promoter methylation of SEPT9 as a potential biomarker for early detection of cervical cancer and its overexpression predicts radioresistance.

Clin Epigenetics 2019 08 19;11(1):120. Epub 2019 Aug 19.

Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, 250012, Shandong, People's Republic of China.

Background: Cervical cancer screening by combined cytology and HPV test has reduced the incidence of cervical cancer, but cytological screening lacks a higher sensitivity while HPV testing possesses a lower specificity. Most patients with invasive cervical cancer are treated with radiotherapy. However, insensitivity to radiotherapy leads to poor efficacy.

Methods: Illumina Methylation EPIC 850k Beadchip was used for genomic screening. We detected methylation of SEPT9 and mRNA expression in different cervical tissues by using methylation-specific PCR and qRT-PCR. Then using CCK8, migration assay, and flow cytometry to detect the biological function and irradiation resistance of SEPT9 in vitro and in vivo. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (CoIP) were used to find the interacting gene with SEPT9. Immunostaining of CD206 in cervical cancer and polarization of macrophages (M2) were evaluated by immunofluorescence and WB. The Cancer Genome Atlas (TCGA) database was used for screening the potential miRNAs induced by SEPT9.

Results: Hyper-methylation of SEPT9 detects cervical cancer and normal tissues, normal+CIN1 and CIN2+CIN3+cancer with high sensitivity and specificity (AUC = 0.854 and 0.797, respectively, P < 0.001). The mRNA and protein expression of SEPT9 was upregulated in cervical cancer tissues when compared to para-carcinoma tissues. SEPT9 promotes proliferation, invasion, migration, and influences the cell cycle of cervical cancer. SEPT9 interacted with HMGB1-RB axis increases irradiation resistance. Furthermore, SEPT9 mediated miR-375 via the tumor-associated macrophages (TAMs) polarization, affecting the resistance to radiotherapy in cervical cancer.

Conclusions: These findings give us the evidence that SEPT9 methylation could be a biomarker for cervical cancer diagnoses. It promotes tumorigenesis and radioresistance of cervical cancer by targeting HMGB1-RB axis and causes polarization of macrophages by mediating miR-375. We suggest SEPT9 could be a potential screening and therapeutic biomarker for cervical cancer.
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http://dx.doi.org/10.1186/s13148-019-0719-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700799PMC
August 2019