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Resistance to PARP inhibitors (PARPi) remains a therapeutic challenge in ovarian cancer patients. PDZ-binding kinase (PBK) participates in the chemoresistance of many malignancies. However, the role of PBK in PARPi resistance of ovarian cancer is obscure. In the current study, we demonstrated that overexpression of PBK contributed to olaparib resistance in ovarian cancer cells. Knockdown of PBK sensitized olaparib-resistant SKOV3 cells to olaparib. Inhibition of PBK using a specific inhibitor enhanced the therapeutic efficiency of olaparib. Mechanically, PBK directly interacted with TRIM37 to promote its phosphorylation and nuclear translocation. which subsequently activates the NFκB pathway. Additionally, PBK enhanced olaparib resistance of ovarian cancer by regulating the NFκB/TRIM37 axis in vitro and in vivo. In conclusion, PBK confers ovarian cancer resistance to PARPi through activating the TRIM37-mediated NFκB pathway, and targeted inhibition of PBK provided the new therapy to improve PARPi treatment outcomes for ovarian cancer patients.

Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) resistance remains a therapeutic challenge in ovarian cancer. High-mobility group box 3 (HMGB3) plays significant roles in the development of drug resistance of many cancers. However, the function of HMGB3 in PARPi resistance is poorly understood. In the current study, we clarified that HMGB3 was aberrantly overexpressed in high-grade serous ovarian carcinoma (HGSOC) tissues, and high HMGB3 levels indicated shorter overall survival and drug resistance in HGSOC. The overexpression of HMGB3 increased the insensitivity of ovarian cancer to PARPi, whereas HMGB3 knockdown reduced PARPi resistance. Mechanistically, PARP1 was identified as a novel interaction partner of HMGB3, which could be blocked using olaparib and was enhanced upon DNA damage conditions. We further showed that loss of HMGB3 induced PARP1 trapping at DNA lesions and inhibited the PARylation activity of PARP1, resulting in an increased DNA damage response and cell apoptosis. The PARPi-resistant role of HMGB3 was also verified in a xenograft mouse model. In conclusion, HMGB3 promoted PARPi resistance via interacting with PARP1, and the targeted inhibition of HMGB3 might overcome PARPi resistance in ovarian cancer therapy.

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.

// Qing Zhang 1,2,* , Wenhui Li 1,5,* , Margaux J. Kanis 3 , Gonghua Qi 1 , Minghao Li 4 , Xingsheng Yang 1 and Beihua Kong 1,2 1 Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Ji’nan, Shandong, P.R. China 2 Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji’nan, Shandong, P.R. China 3 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 4 Shandong University School of Medicine, Ji’nan, Shandong, P.R. China 5 Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China * These authors have contributed equally to this work Correspondence to: Beihua Kong, email: // Xingsheng Yang, email: // Keywords : conization, radical trachelectomy, early cervical cancer, fertility-sparing treatment, live births Received : November 04, 2016 Accepted : February 06, 2017 Published : March 15, 2017 Abstract OBJECTIVE: The objectives of this study were to evaluate the rates of recurrence, survival and pregnancy, and characterize pregnancy outcomes of early-stage cervical cancer(eCC) treated with fertility-sparing methods such as cervical conization (CON) and radical trachelectomy(RT) with or without pelvic lymphadenectomy. STUDY DESIGN: This was a meta-analysis of observational studies analyzed by a random-effects model and a meta-regression to assess heterogeneity. RESULTS: Sixty observational studies encompassing 2,854 patients were included; 17 of which evaluated CON and 43 RT. Three hundred and seventy-five patients were included in the CON group: 176(46.9%) stage IA1 and 167(44.5%) stage IB1. In the RT group, 2479 cases were included: 143(6.0%) stage IA1, 299(12.1%) stage IA2, 1987(79.9%) stage IB1. CON was performed in 347(92.5%) cases, resulting in a recurrence rate of 0.4%(95%CI: 0.0%-1.4%), a death rate of 0%(0%-0%), a pregnancy rate of 36.1%(26.4%-46.2%), a spontaneous abortion rate of 14.8%(9.3%-21.2%) and a preterm delivery rate of 6.8%(1.5%-15.5%). For the RT group, 2273(91.7%) underwent successful surgeries with a recurrence rate of 2.3%(1.3%-3.4%),a death rate of 0.7%(0.3%-1.1%), a pregnancy rate of 20.5%(16.8%-24.5%), a spontaneous abortion rate of 24.0%(18.8%-29.6%) and a preterm delivery rate of 26.6%(19.6%-34.2%). From a subgroup analysis, the recurrence rates for stage IA tumors treated with CON and RT were 0.4%(0.0%-1.9%) and 0.7%(0.0%-2.3%), respectively; and for stage IB were 0.6%(0.0%-2.7%) and 2.3%(0.9%-4.1%). CONCLUSION: Fertility-sparing treatment including CON or RT for eCC is feasible and carefully selected women can preserve fertility and achieve pregnancy resulting in live births. CON seems to result in better pregnancy outcomes than RT with similar rates of recurrence and mortality.

// Qing Zhang 1, 2, * , Gonghua Qi 1, 4, * , Margaux J. Kanis 3 , Ruifen Dong 1 , Baoxia Cui 1 , Xingsheng Yang 1 and Beihua Kong 1, 2 1 Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Ji’nan, Shandong, 250012, P.R. China 2 Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji’nan, Shandong, 250012, P.R. China 3 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA 4 School of Medicine, Shandong University, Ji’nan, Shandong, 250012, P.R. China * These authors contributed equally to this work Correspondence to: Beihua Kong, email: kongbeihua@sdu.edu.cn Keywords: endometrial carcinoma, complex atypical hyperplasia, fertility-sparing therapy, hysteroscopic resection, oral progestogens Received: December 15, 2016 Accepted: April 05, 2017 Published: May 03, 2017 ABSTRACT Objective: To compare fertility-sparing therapies including oral progestogens, hysteroscopic resection (HR), and the levonorgestrel- releasing intrauterine system (LNG-IUS) in achieving disease regression, recurrence and live birth rate in well differentiate early-stage endometrial carcinoma (eEC) and complex atypical hyperplasia(CAH). Study Design: This was a meta-analysis of previous studies focus on the fertility-sparing therapy for well differentiate early-stage endometrial carcinoma (eEC) and complex atypical hyperplasia (CAH). Date Sources: Medline, the Cochrane Library and Embase was searched with the terms and Synonyms: words similar to eEC and CAH with therapies associated with fertility-sparing. Main Outcome Measures: The number of all patients accepted fertility sparing therapies, patients got regressed, relapsed and delivered were extracted from each study, and the regression, recurrence, and live birth rate of each study were calculated. The regression, recurrence and live birth rates between each two interventions were compared with the aid of meta-regression in packages of “meta” and ”meta for” written in R. Results: Fifty-four studies reported fertility sparing therapies in young women with eEC and CAH were included. Meta-analysis showed that HR followed by progestogens achieved a higher pooled regression (98.06% vs 77.20% P < 0.0001) and live birth rate (52.57% vs 33.38%, P = 0.0944) and a lower recurrence rate compared with oral progestogens alone (4.79% vs 32.17% P = 0.0004). At the same time, the pooled live birth rate (52.57% vs 18.09% P =0.0399) of HR followed by progestogens are significantly higher than the LNG-IUS alone. Which no statistical difference in regression (98.06% vs 94.24%; P = 0.4098) and recurrence rates (4.79% vs 3.90% P = 0.8561) was seen. Conclusions: Of the available fertility-sparing therapeutic options, HR followed by progestogens may be a more effective one.