Targeting TCF19 sensitizes MSI endometrial cancer to anti-PD-1 therapy by alleviating CD8+ T cell exhaustion via TRIM14-IFN-ß axis.

Immune checkpoint blockade (ICB) therapies display clinical efficacy in microsatellite instable (MSI) endometrial cancer (EC) treatment, the key mechanism of which is reversing T cell exhaustion and restoration of anti-tumor immunity. Here, we demonstrate that transcription factor 19 (TCF19), one of the most significantly differentially expressed genes between MSI and microsatellite stable (MSS) patients in The Cancer Genome Atlas (TCGA)-EC cohort, is associated with poor prognosis and immune exhaustion signature. Specifically, TCF19 is significantly elevated in MSI EC, which in turn promotes tripartite motif-containing 14 (TRIM14) transcription and correlates with hyperactive signaling of the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3)-interferon ß (IFN-ß) pathway. The TCF19-TRIM14 axis promotes tumorigenicity under non-immunological background, and the enhanced downstream secretion of IFN-ß facilitates CD8+ T cell exhaustion through cell differentiation reprogramming. Finally, using humanized models, we show that a combination of TCF19 inhibition and ICB therapy demonstrates more effective anti-tumor responses. Together, our study indicates that targeting TCF19 is a potent strategy for alleviating CD8+ T cell exhaustion and synergizing with ICB in tumor treatment.

HMGB3 promotes the malignant phenotypes and stemness of epithelial ovarian cancer through the MAPK/ERK signaling pathway.

BACKGROUND: Ovarian cancer, particularly epithelial ovarian cancer (EOC), is the leading cause of cancer-related mortality among women. Our previous study revealed that high HMGB3 levels are associated with poor prognosis and lymph node metastasis in patients with high-grade serous ovarian carcinoma; however, the role of HMGB3 in EOC proliferation and metastasis remains unknown. METHODS: MTT, clonogenic, and EdU assays were used to assess cell proliferation. Transwell assays were performed to detect cell migration and invasion. Signaling pathways involved in HMGB3 function were identified by RNA sequencing (RNA-seq). MAPK/ERK signaling pathway protein levels were evaluated by western blot. RESULTS: HMGB3 knockdown inhibited ovarian cancer cell proliferation and metastasis, whereas HMGB3 overexpression facilitated these processes. RNA-seq showed that HMGB3 participates in regulating stem cell pluripotency and the MAPK signaling pathway. We further proved that HMGB3 promotes ovarian cancer stemness, proliferation, and metastasis through activating the MAPK/ERK signaling pathway. In addition, we demonstrated that HMGB3 promotes tumor growth in a xenograft model via MAPK/ERK signaling. CONCLUSIONS: HMGB3 promotes ovarian cancer malignant phenotypes and stemness through the MAPK/ERK signaling pathway. Targeting HMGB3 is a promising strategy for ovarian cancer treatment that may improve the prognosis of women with this disease. Video Abstract.

PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer.

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.

HMGB3 promotes PARP inhibitor resistance through interacting with PARP1 in ovarian cancer.

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.

Clinical features and prognostic factors analysis of intravenous leiomyomatosis.

Background: The treatment and prognostic factors of intravenous leiomyomatosis (IVL) remain lacking systematic evidence. Methods: A retrospective study was conducted on IVL patients from the Qilu Hospital of Shandong University, and IVL cases were published in PubMed, MEDLINE, Embase and Cochrane Library databases. Descriptive statistics were used for the basic characteristics of patients. The Cox proportional hazards regression analysis was used to assess the high-risk factors related to the progression-free survival (PFS). The comparison of survival curves was performed by Kaplan-Meier analysis. Results: A total of 361 IVL patients were included in this study, 38 patients from Qilu Hospital of Shandong University, and 323 patients from the published literature. Age ≤45 years was observed in 173 (47.9%) patients. According to the clinical staging criteria, stage I/II was observed in 125 (34.6%) patients, and stage III/IV was observed in 221 (61.2%) patients. Dyspnea, orthopnea, and cough were observed in 108 (29.9%) patients. Completed tumor resection was observed in 216 (59.8%) patients, and uncompleted tumor resection was observed in 58 (16.1%) patients. Median follow-up period was 12 months (range 0-194 months), and 68 (18.8%) recurrences or deaths were identified. The adjusted multivariable Cox proportional hazard analysis showed age ≤45 years (vs. >45) (hazard ratio [HR] = 2.09, 95% confidence interval [CI] 1.15-3.80, p = 0.016), and uncompleted tumor resection (vs. completed tumor resection) (HR = 22.03, 95% CI 8.31-58.36, p < 0.001) were high-risk factors related to the PFS. Conclusion: Patients with IVL have a high probability of recurrence after surgery and a poor prognosis. Patients younger than 45 years and with uncompleted tumor resection are at higher risk of postoperative recurrence or death.

TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway.

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. However, the molecular mechanisms underlying HGSOC development, progression, chemotherapy insensitivity and resistance remain unclear. Two independent GEO datasets, including the gene expression profile of primary ovarian carcinoma and normal controls, were analyzed to identify genes related to HGSOC development and progression. A KEGG pathway analysis of the differentially expressed genes (DEGs) revealed that the cell cycle pathway was the most enriched pathway, among which TTK protein kinase (TTK) was the only gene with a clinical-grade inhibitor that has been investigated in a clinical trial but had not been studied in HGSOC. TTK was also upregulated in cisplatin-resistant ovarian cancer cells from two other datasets. TTK is a regulator of spindle assembly checkpoint signaling, playing an important role in cell cycle control and tumorigenesis in various cancers. However, the function and regulatory mechanism of TTK in HGSOC remain to be determined. In this study, we observed TTK upregulation in patients with HGSOC. High TTK expression was related to a poor prognosis. Genetic and pharmacological inhibition of TTK impeded the proliferation of ovarian cancer cells by disturbing cell cycle progression and increasing apoptosis. TTK silencing increased cisplatin sensitivity by activating the mammalian target of rapamycin (mTOR) complex to further suppress cisplatin-induced autophagy in vitro. In addition, the enhanced sensitivity was partially diminished by rapamycin-mediated inhibition of mTOR in TTK knockdown cells. Furthermore, TTK knockdown increased the toxicity of cisplatin in vivo by decreasing autophagy. These findings suggest that the administration of TTK inhibitors in combination with cisplatin may lead to improved response rates to cisplatin in patients with HGSOC presenting high TTK expression. In summary, our study may provide a theoretical foundation for using the combination therapy of cisplatin and TTK inhibitors as a treatment for HGSOC in the future.

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

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.

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

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.

PBK, targeted by EVI1, promotes metastasis and confers cisplatin resistance through inducing autophagy in high-grade serous ovarian carcinoma.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal type of gynecologic malignancy. Chemoresistance is the main reason for the poor prognosis of HGSOC. PDZ-binding kinase (PBK) promotes the malignant progression of various carcinomas. However, the roles and clinical significance of PBK in HGSOC remain unclear. Here, we reported that PBK was overexpressed in HGSOC tissues and cell lines. High PBK expression was associated with a poor prognosis, metastasis, and cisplatin resistance of HGSOC. Overexpression of PBK promoted autophagy and enhanced cisplatin resistance via the ERK/mTOR signaling pathway. Further study showed that inhibition of autophagy by chloroquine or bafilomycin A1 reversed PBK-induced cisplatin resistance. Overexpression of PBK decreased ovarian cancer responsiveness to cisplatin treatment through inducing autophagy in vivo. We also demonstrated that the PBK inhibitor OTS514 augmented the growth inhibition effect of cisplatin in vitro and in vivo. Moreover, ecotropic viral integration site-1 (EVI1) could regulate PBK expression through directly targeting the PBK promoter region. In conclusion, high PBK expression was correlated with a poor prognosis, metastasis, and cisplatin resistance through promoting autophagy in HGSOC. PBK might be a promising target for the early diagnosis and individual treatment of ovarian cancer.

Comparison among fertility-sparing therapies for well differentiated early-stage endometrial carcinoma and complex atypical hyperplasia.

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.

Oncologic and obstetrical outcomes with fertility-sparing treatment of cervical cancer: a systematic review and meta-analysis.

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.