RESUMEN
The BRCA1/2 gene is important for assessing the risk of familial/hereditary ovarian cancer (OC). This case is a patient with OC, and two of her immediate family members are cancer patients. We sequenced the coding and splicing regions of 42 OC susceptibility genes, and found a rare pathogenic splicing mutation BRCA1:c.132C > T (p.cys44 =) in 2 patients. Although the mutation is synonymous, software prediction and functional verification have shown that it affects alternative splicing and leads to frameshift mutations (c.131_134del). Chromosome microarray analysis of the tissue samples revealed the presence of a BRCA1 gene deletion with a fragment size of 1.42 Mb and an HRD score of 71. In addition, the proband showed a sensitive response to platinum treatment. This case suggests the clinical significance of OC susceptibility genes sequencing and HRD scoring in screening hereditary OC families.
Asunto(s)
Predisposición Genética a la Enfermedad , Mutación/genética , Neoplasias Ováricas/genética , Empalme del ARN/genética , Secuencia de Bases , Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
The AURELIA trial demonstrated that adding Bevacizumab to chemotherapy significantly improved progression-free survival (PFS) for platinum resistant recurrent ovarian cancer. Recently, immunotherapy also presented potential anti-tumor effects in several malignant solid tumors. This study aimed to investigate whether combining anti-PD-L1 Atezolizumab with BEV may have a synergistic effect and enhance the efficacy of both treatments in cisplatin resistant epithelial ovarian cancer (CREOC). We retrospectively analyzed 124 epithelial ovarian cancer (EOC) patients from Gynecologic Oncology Department of Tianjin Cancer Hospital between January 2013 and June 2018, who all were diagnosed with cisplatin resistance due to progressing <6 months after completing platinum-based therapy. Based on responding to at least 2 cycles of Bevacizumab-containing chemotherapy (BC), these Patients were divided into BC response group and BC non-response group. Immunohistochemistry was used to detect that PD-L1 expression and tumor angiogenesis-related proteins (VEGF and Semaphorin4D) in tissues from 124 patients with CREOC. The positive expressions of PD-L1, VEGF, and Semaphorin4D (SEMA4D) were found in 58.73, 50.79, and 71.43% of the 63 cases CREOC tissues with BC response, respectively, which were significantly higher than that in the 61 cases BC non-response group (P < 0.05). PD-L1 expression correlated with SEMA4D and VEGF positively (r = 0.344 and 0.363, P < 0.001). Over-expressions of PD-L1, VEGF and SEMA4D are associated with more malignant clinicopathologic characteristics of CREOC Patients. In survival analysis, patients' response to BC was the independent factor for evaluation of PFS and overall survival (OS). Cell functional assays showed that Atezolizumab in combination with Bevacizumab inhibited the proliferation, migration, and invasion of cisplatin resistant ovarian cancer cell line A2780cis in vitro synergistically, which maybe associate with Bevacizumab suppressing the epithelial-mesenchymal transition (EMT) and PD-L1 expression by targeting STAT3. Furthermore, Bevacizumab and Atezolizumab induced synergistic anti-tumor effect in vivo. These findings suggest a novel therapeutic strategy for cisplatin resistant recurrent EOC and its mechanism warrants further study.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Antígenos CD/metabolismo , Apoptosis/efectos de los fármacos , Antígeno B7-H1/antagonistas & inhibidores , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cisplatino/uso terapéutico , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Femenino , Humanos , Persona de Mediana Edad , Invasividad Neoplásica/patología , Neoplasias Ováricas/patología , Supervivencia sin Progresión , Estudios Retrospectivos , Factor de Transcripción STAT3/antagonistas & inhibidores , Semaforinas/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: Emerging evidence indicates that long non-coding RNAs (lncRNAs) are critical in carcinogenesis and progression of ovarian cancer. This study aimed to explore the functions and molecular mechanisms of plasmacytoma variant translocation I (PVT1) in ovarian cancer. METHODS: PVT1 and miR-214 were detected by qRT-PCR assays in ovarian cancer tissues and cells. The cell proliferation, migration, and invasion abilities were detected by cell functional experiments, respectively. Western blot assay was performed to detect epithelial-mesenchymal transition (EMT) markers. MiR-214 expression regulated by PVT1 was studied by RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays. RESULTS: The expression of PVT1 was up-regulated in ovarian cancer tissues and cell lines. Elevated PVT1 expression was associated with advanced stage and indicated poor prognosis for ovarian cancer patients. The knockdown of PVT1 impaired SKOV3 cell proliferation, migration, and invasion in vitro. The promotion of ovarian cancer progression by PVT1 involved in regulation of the epithelial-mesenchymal transition process and PVT1 interaction with EZH2 represses miR-214 expression in ovarian cancer cells. CONCLUSIONS: PVT1 plays an important role in ovarian cancer tumorigenesis, which might be as a novel diagnostic marker and therapeutic target for ovarian cancer.
RESUMEN
Current evidences indicate that the fallopian tube plays a major role in the pathogenesis of epithelial ovarian cancer (EOC). Salpingectomy represents a novel and potentially effective risk-reducing option. In this study, there were 1822 patients diagnosed and treated for EOC or primary peritoneal cancer (PPC) at Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital from January 1, 2007 to April 30, 2017. Among them, 198 patients with a history of gynecological surgery because of benign diseases were enrolled to analyze further. Using 1:2 case-control study, we found that the incidence of EOC was significantly decreased in the population with salpingectomy, compared to women with fallopian tube reserved (P<0.05). At the same period, there were 4339 patients receiving opportunistic salpingectomy in our centre because of benign gynecological diseases. The results showed the rate of bilateral salpingectomy was annually increased from 2007 to 2017 (22.02% to 60.22%), which showed approximately threefold increase in a decade. In general, factors affecting the rate of salpingectomy included age, child number, menopause or not, marital status, educational status, income status, and with or without family history of tumor. Therefore, based on ten years experiences from our centre, it is recommended that physician should discuss with appropriate patients to perform opportunistic bilateral salpingectomy at the time of receiving benign gynecological surgery for preventing ovarian cancer. Moreover, the prospective, large scale and multi-centre studies to evaluate the safety and efficacy of salpingectomy as a preventive strategy for ovarian cancer warrant to conduct in the future.
RESUMEN
Tumor metastasis is a prominent cause of treatment failure in cervical carcinoma. Phenethyl isothiocyanate (PEITC) is an active component extracted from cruciferous plants that has exhibited anticancer activity in various types of human cancer; however, its effect on the inhibition of metastasis remains unclear. The current study aimed to explore the effect of PEITC on the suppression of metastasis in HeLa cervical carcinoma cells. Multiple variables were assessed with different methods as follows: Cell viability, with a ViCELL analyzer; cell adhesion, by MTS assay; cell invasion, by Transwell assay; cell cycle, by flow cytometry assay; cytokine concentration, by ELISA assay; metastasisrelated gene and protein expression, by quantitative polymerase chain reaction and western blotting; and transcription factor activity, by gene reporter assay. The results indicated that PEITC exhibited an inhibitory effect on the adhesion and invasion of HeLa cells by induction of G2/M phase arrest, it reduced the expression of CDK1, MMP2/9, CD44, ICAM1, increased the production of TGFß, IL6 and IL8, and increased the phosphorylation of Smad2. These results suggest that PEITC may be a potential antitumor compound, acting through the TGFß/Smad2 pathway; and it has the potential for future use as a therapy for cervical carcinoma subsequent to further studies.
Asunto(s)
Antineoplásicos/farmacología , Isotiocianatos/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adhesión Celular , Puntos de Control del Ciclo Celular , Movimiento Celular , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Interleucina-6/biosíntesis , Interleucina-8/biosíntesis , Invasividad Neoplásica , Metástasis de la Neoplasia , Transducción de Señal/efectos de los fármacos , Proteína Smad2/metabolismo , Factor de Crecimiento Transformador beta/biosíntesis , Neoplasias del Cuello Uterino/patologíaRESUMEN
Folic acid and methylenetetrahydrofolate reductase (MTHFR) may affect the development of human cancer. However, few studies have evaluated folate intake and MTHFR in susceptibility to and prognosis of patients with ovarian cancer. We conducted a prospective case-control study in 215 ovarian cancer patients and 218 controls (all Chinese) between Jan. 2004 and Jan. 2007. MTHFR C677T genotyping was done by PCR-RFLP. All patients were followed up until Dec. 2010. We found a 2.43-fold increased risk of ovarian cancer among MTHFR 677TT carriers, and a decreased risk of ovarian cancer in individuals with high folate intake (OR = 0.54, 95% CI = 0.32-0.94). Cox regression survival analysis showed that among the ovarian cancer patients, those carrying the 677TT genotype had a higher risk of death (HR = 2.17, 95% CI = 1.20-4.79), while high folate intake was associated with a lower risk of death (HR = 0.43, 95% CI = 0.33-0.88). Moreover, MTHFR 677CC carriers with higher folate intake showed a lower risk of death from ovarian cancer (HR = 0.32, 95% CI = 0.27-0.82). In summary, high folate intake may lessen susceptibility and improve the prognosis of ovarian cancer patients, while the MTHFR 677TT genotype appears to increase ovarian cancer risk and worsen its prognosis in a Chinese population.