RNA-binding protein THUMPD2 inhibits proliferation and promotes metastasis in epithelial ovarian cancer.

Ovarian cancer (OC) is a common and lethal gynaecological malignancy. RNA-binding proteins (RBPs) play a crucial role in governing RNA metabolism and have been implicated in the development and progression of diverse cancer types. Slight alterations in RBPs' expression or activity can induce substantial modifications in the regulatory network. THUMPD2, as member of the RBP family, was found to have differential expression in ovarian cancer, with the mechanism has not been studied yet. In this study, THUMPD2 protein was found to be weakly expressed in the early (I + II) stages of OC (P = 0.013), with a low expression rate of 78.6 %, and highly expressed in late (III + IV) stages (P = 0.009), with a high expression rate of 84.8 %. The shRNA-mediated knockdown of THUMPD2 in OVCAR3 and SKOV3 cells resulted in increased cell proliferation but inhibited metastasis, whereas THUMPD2 overexpression had the opposite effect. THUMPD2 overexpression suppressed tumour growth in vivo. Conversely, low THUMPD2 expression promoted tumour growth. Furthermore, we identified the potential target genes and pathways of THUMPD2 using GO and KEGG analyses, which were related to the centrosome, microtubules, cell cycle, and extracellular matrix. We demonstrated that low expression of THUMPD2 in the early stage promoted tumour growth and high expression in the late stage promoted tumour metastasis. Our findings reveal the dual function of THUMPD2 in OC and suggest that THUMPD2 may serve as a therapeutic target for the treatment of OC.

Efficacy and Safety of Niraparib as First-Line Maintenance Treatment for Patients with Advanced Ovarian Cancer: Real-World Data from a Multicenter Study in China.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors are a new maintenance therapy option for patients with ovarian cancer (OC). OBJECTIVE: To evaluate the efficacy and influencing factors of the novel PARP inhibitor niraparib for maintenance treatment of Chinese patients with advanced OC. PATIENTS AND METHODS: In this retrospective multicenter real-world study patients with advanced OC from 15 hospitals throughout China were enrolled. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included the time to treatment discontinuation and safety. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to identify possible risk factors for PFS, after which a prediction model was established to evaluate the likelihood of achieving an 18-month PFS. The relationship between the dose of niraparib and PFS was also evaluated. RESULTS: The PFS rates of 199 patients at 6, 12, 18, 24, and 30 months were 87.4%, 75.9%, 63.6%, 56.1%, and 51.8%, respectively. LASSO regression model revealed that only age < 65 years (P = 0.011), BRCA mutations (P < 0.001), and R0 status after cytoreductive surgery (P = 0.01) were significant factors associated with prolonged PFS times. Based on the LASSO logistic regression analysis, a clinical prediction formula was developed: - 2.412 + 1.396Age≥65yr + 2.374BRCAwt + 1.387R1 + 0.793Interval≥12w + 0.178BMI>24kg/m2 which yielded a cut-off value of 0.091, an area under the curve (AUC) of 0.839 (0.763-0.916), a sensitivity of 94.3%, and an accuracy of 78.5%. A nomogram was then built to visualize the results. The major treatment-emergent adverse events of ≥ grade 3 included a platelet count decrease (19.1%), white blood cell count decrease (15.1%), neutrophil count decrease (13.1%), and anemia (18.6%). The 18-month PFS rates in patients treated with 200 mg niraparib were somewhat higher than in patients treated with 100 mg after 3-months of therapy. CONCLUSIONS: For Chinese OC patients, niraparib, particularly at a 200 mg individual starting dose, was an effective therapy with easily manageable safety.

Maintenance therapy with poly (ADP-ribose) polymerase inhibitors is a new option for patients with ovarian cancer (OC) after they have received platinum-based chemotherapy to reduce the recurrence or relapse rates, but it remains unclear whether there are any changes in efficacy and safety when different starting doses of niraparib are administrated to Chinese patients, who typically have a bodyweight < 77 kg. We found that niraparib exhibited satisfactory efficacy with tolerable safety during maintenance therapy for advanced OC whether administered at 100 mg or 200 mg doses. We believe these regimens can serve as a valuable addition to the previous results of randomized controlled trials.

Role of DEP domain-containing protein 1B (DEPDC1B) in epithelial ovarian cancer.

Aberrant expression of DEPDC1B (DEP domain-containing protein 1B) has been shown to be associated with various types of malignant tumors. However, little is known about the role of DEPDC1B in epithelial ovarian cancer (EOC). The purpose of this study was to investigate the expression and role of DEPDC1B in EOC. Immunohistochemical staining of 60 high-grade serous ovarian cancer (HGSOC) showed that DEPDC1B expression was associated with response to first line chemotherapy, and DEPDC1B expression was higher in platinum-resistant patients than in platinum-sensitive patients. However, there was no association between DEPDC1B expression and age, preoperative CA125 level, ascites status, location, FIGO stage, and residual disease. Furthermore, our study demonstrated that increased DEPDC1B expression was correlated with reduced overall survival (OS) and progression-free survival (PFS) time in patients with HGSOC. Multivariate analysis showed that DEPDC1B independently predicted OS in patients with HGSOC. However, DEPDC1B expression was not an independent prognostic factor for PFS in patients with HGSOC. Moreover, our study demonstrated that DEPDC1B could promote the proliferation of OVCAR3 and SKOV3 cells by enhancing AKT phosphorylation at Ser473. Treatment with MK2206 and LY294002 significantly suppressed cell proliferation that is induced by DEPDC1B up-regulation in both OVCAR3 and SKOV3 cells. Together, these results revealed that DEPDC1B was an independent prognostic factor for OS in patients with HGSOC, and DEPDC1B may promote the proliferation of EOC cells via enhancing AKT phosphorylation at Ser473.

Serum CCAT2 as a biomarker for adjuvant diagnosis and prognostic prediction of cervical cancer.

Growing evidence indicates that lncRNA colon cancer-associated transcript 2 (CCAT2) is associated with cancers. However, the clinical value of CCAT2 in cervical cancer (CC) remains unclear. In this study, serum CCAT2 level was detected by real-time quantitative PCR (RT-qPCR). Carbohydrate antigen 125 (CA125) and squamous-cell carcinoma antigen (SCC) were detected by electrochemiluminescence. A receiver operating characteristic (ROC) curve was utilized to estimate the diagnostic efficiency of CCAT2. Kaplan-Meier survival analysis and univariable and multivariable analyses were performed to assess the prognostic value of CCAT2. The relative expression level of CCAT2 in primary CC patients was significantly higher than that in cervical intraepithelial neoplasias (CIN) patients and healthy controls (both P < 0.001). CCAT2 relative expression was positively correlated with tumor Federation of Gynecology and Obstetrics (FIGO) stage, SCC-Ag and lymph node metastasis (LNM) (all P < 0.05). CCAT2 expression in recurrent/metastatic CC was significantly higher compared with primary CC (P < 0.0001) or operated CC (P < 0.0001) and during follow-up, CCAT2 expression was increased before surgery and decreased significantly after surgery (P < 0.0001). Furthermore, the overall survival rate of CC patients with high CCAT2 expression group markedly decreased as compared with that of low CCAT2 expression group (P = 0.026). Univariate analyses indicated that CCAT2 was a poor prognostic factor associated with overall survival (OS). Our study indicates that CCAT2 may be valuable in complementary diagnosis and monitoring of progression and prognosis of CC patients. Combined detection of CCAT2, CA125 and SCC can greatly improve the diagnostic efficiency of primary CC.

Genetic variants within 17q12 are associated with the risk of cervical cancer in the Han Chinese population.

Chromosome 4q12 and 17q12 have been identified as two regions associated with susceptibility to cervical cancer in a genome-wide association study. To identify potential causal variants within these two regions, we conducted a case-control study including 1486 patients with cervical cancer and 1536 age-matched (±5 years) healthy controls. Based on RegulomeDB database, 12 potentially functional variants were selected and then genotyped by using Sequenom MassARRAY. Univariate and multivariate logistic regression models were used to evaluate the associations. We found that the G allele of rs8076131 and the A allele of rs12150079 in 17q12 region were significantly associated with increased risk of cervical cancer (adjusted OR = 1.15, 95% CI = 1.02-1.30, P = 0.02 for rs8076131; adjusted OR = 1.19, 95% CI = 1.03-1.36, P = 0.02 for rs12150079). Individuals with 3-4 risk alleles of these two variants had 24% higher odds of cervical cancer than those without the risk alleles (OR = 1.24, 95% CI = 1.07-1.44, P < 0.01). The stratified analysis showed that the associations of rs8076131 and rs12150079 with cervical cancer risk were statistically significant in subgroups of older menarche age (>16 years), more parities (≥2), nonsmokers, and having no family cancer history, but the test results for subgroup heterogeneity were not significant. The current study provides the evidence that rs8076131 and rs12150079 in 17q12 region may contribute to cervical cancer susceptibility in the Han Chinese population.

Independent prognostic role of human papillomavirus genotype in cervical cancer.

BACKGROUND: Although the correlation of HPV genotype with cervical precursor lesions and invasive cancer has been confirmed, the role of HPV genotype in cervical cancer prognosis is less conclusive. This study aims to systematically investigate the independent prognostic role of HPV genotype in cervical cancer. METHODS: A total of 306 eligible patients provided cervical cell specimens for HPV genotyping before therapy and had a median follow-up time of 54 months after diagnosis. Survival times were measured from the date of diagnosis to the date of cervical cancer-related death (overall survival, OS) and from the date of diagnosis to the date of recurrence or metastasis (disease free survival, DFS). Log-rank tests and Cox proportional hazard models were performed to evaluate the association between HPV genotype and survival times. RESULTS: A total of 12 types of high-risk HPV were detected and the leading ten types belong to two species: alpha-9 and alpha-7. HPV16 and 18 were the two most common types, with the prevalence of 60.8% and 8.8%, respectively. In the univariate analysis, HPV16-positive cases were associated with better OS (P = 0.037) and HPV16-related species alpha-9 predicted better OS and DFS (both P < 0.01). After adjusting for age, FIGO stage, and therapy, HPV16 showed a hazard ratio (HR) of 0.36 (95% CI: 0.18, 0.74; P = 0.005) for OS, and alpha-9 resulted in a HR of 0.17 (95% CI: 0.08, 0.37; P < 0.001) for OS and 0.32 (95% CI: 0.17, 0.59; P < 0.001) for DFS. CONCLUSIONS: HPV genotype poses differential prognoses for cervical cancer patients. The presence of HPV16 and its related species alpha-9 indicates an improved survival.

Genetic variants within microRNA-binding site of RAD51B are associated with risk of cervical cancer in Chinese women.

RAD51B plays a central role in homologous recombinational repair (HRR) of DNA double-strand breaks (DSBs), which is important to prevent genomic instability, a hallmark of cancer. Recent studies suggested that common genetic variants of RAD51B may contribute to cancer susceptibility. In this study, we aimed to investigate whether potentially functional variants within miRNA-binding sites of RAD51B are associated with risk of cervical cancer. A total of 1486 cervical cancer patients and 1536 cancer-free controls were enrolled, and two genetic variants, rs963917 (A > G) and rs963918 (T > C), were genotyped in all participants. Using multivariate logistic regression analyses, we found that G allele of rs963917 conferred lower risk of cervical cancer compared to A allele (adjusted OR = 0.89, 95% CI = 0.80-0.99, P = 0.039). Similarly, rs963918 allele C was associated with a decreased risk for cervical cancer compared with allele T (adjusted OR = 0.84, 95% CI = 0.74-0.94, P = 0.004). Haplotype analyses showed that haplotype GC was also correlated with lower risk (OR = 0.83, 95% CI = 0.73-0.95, P = 0.005) compared with the most common haplotype AT. In summary, our study suggested that miRNA-binding site genetic variants of RAD51B may modify the susceptibility to cervical cancer, which is important to identify individuals with differential risk for this malignancy and to improve the effectiveness of preventive intervention.

Expression quantitative trait loci in long non-coding RNA PAX8-AS1 are associated with decreased risk of cervical cancer.

Paired box 8 (PAX8) is a crucial nephric-lineage transcription factor, and its aberrant expression has been detected in various types of cancer including Müllerian carcinomas. PAX8 antisense RNA 1 (PAX8-AS1), a potential regulator of PAX8, contains specific single nucleotide polymorphisms (SNPs) that may represent expression quantitative trait loci (eQTLs) for PAX8. In this study, we hypothesized that these eQTLs SNPs in PAX8-AS1 may influence the risk of cervical cancer. A case-control study of 1486 cervical cancer patients and 1536 cancer-free controls was conducted to identify the associations between two eQTLs SNPs (rs4848320 and rs1110839) and cervical cancer. Logistic regression analyses revealed that variant allele T of rs4848320 (recessive model: adjusted OR = 0.61, 95 % CI = 0.38-0.97, P = 0.027) and G of rs1110839 (additive model: adjusted OR = 0.88, 95 % CI = 0.79-0.99, P = 0.032) were associated with decreased risk of cervical cancer. Moreover, the haplotype containing variant alleles of the two SNPs significantly decreased the risk of cervical cancer compared to the most frequent haplotype (adjusted OR = 0.82, 95 % CI = 0.70-0.95, P = 0.009). These findings indicate that PAX8 eQTLs SNPs may serve as novel susceptibility markers for cervical cancer.

HLA-DP is the cervical cancer susceptibility loci among women infected by high-risk human papillomavirus: potential implication for triage of human papillomavirus-positive women.

Given that only a small proportion of women infected by high-risk human papillomavirus (hrHPV) develop cervical cancer, it's important to identify biomarkers for distinguishing women with hrHPV positivity who might develop cervical cancer from the transient infections. In this study, we hypothesized that human leukocyte antigens (HLA) susceptibility alleles might contribute to cervical cancer risk among females infected by hrHPV, and interact with hrHPV types. A case-control study with 593 cervical cancer cases and 407 controls (all hrHPV positive) was conducted to evaluate the effect of eight HLA-related single-nucleotide polymorphisms (SNPs) and their interactions with hrHPV types on the risk of cervical cancer. Three HLA-DP SNPs (rs4282438, rs3117027, and rs3077) were found to be significantly associated with risk of cervical cancer (rs4282438: odds ratio (OR) = 0.72, 95 % confidence interval (CI) = 0.56-0.93; rs3117027: OR = 1.41, 95 % CI = 1.10-1.83; and rs3077: OR = 1.37, 95 % CI = 1.04-1.80) among women infected with hrHPV. An additive interaction between HPV16 and rs4282438 for cervical cancer risk was also found (P for interaction = 0.002). Compared with subjects carrying variant genotypes (GG/TG) and non-HPV16 infections, those carrying wild-type genotype (TT) of rs4282438 and HPV16 positive had a 5.22-fold increased risk of cervical cancer (95 % CI = 3.39-8.04). Our study supported that certain HLA-DP alleles in concert with HPV16 could have a predisposition for cervical cancer development, which may be translated for triage of hrHPV-positive women.