Nasopharyngeal carcinoma (NPC) is a common cancer found in the nasopharynx, which plagues countless NPC patients. MicroRNA-372 (miR-372) has been reported to be involved in various tumors. Here, we explored the important role of miR-372 in radiosensitivity, invasion, and metastasis of NPC. Microarray analysis was conducted to search the NPC-related differentially expressed genes (DEGs) and predict the miRs regulating PBK, which suggested that miR-372 could influence the development of NPC via PBK and the p53 signaling pathway. Importantly, miR-372 was observed to target PBK, thus down-regulating its expression. Then, NPC 5-8F and C666-1 cells were selected, and treated with ionization radiation and alteration of miR-372 and PBK expression to explore the functional role of miR-372 in NPC. The expression of miR-372, PBK, Bcl-2, p53, and Bax as well as the extent of Akt phosphorylation were measured. In addition, cell colony formation, cell cycle, proliferation, apoptosis, migration, and invasion were detected. At last, tumor growth and the effect of miR-372 on radiosensitivity of NPC were evaluated. Besides, over-expressed miR-372 down-regulated Bcl-2 and PBK expression and the extent of Akt phosphorylation while up-regulated the expression of p53 and Bax. Additionally, miR-372 over-expression and radiotherapy inhibited cell clone formation, proliferation, tumor growth, migration, invasion, and cell cycle entry, but promoted cell apoptosis. However, the restoration of PBK in NPC cells expressing miR-372 reversed the anti-tumor effect of miR-372 and activation of the p53 signaling pathway. In conclusion, the study shows that up-regulated miR-372 promotes radiosensitivity by activating the p53 signaling pathway via inhibition of PBK.
The relationship between risk of esophageal squamous cell carcinoma (ESCC) and adult height, changes in individual body mass index (BMI) and body shape is not established. We performed a large population-based case-control study, which enrolled a total of 1414 ESCC cases and 1989 controls in a high-incidence area in China. Using face-to-face interview with a structured questionnaire, information on participants' heights, weights, and perceived body shapes at 20 years of age was collected. Additionally, data on weight and perceived body shape among the same participants 10 years prior to ascertainment were collected using the same method. Odd ratios (ORs) of ESCC risk in relation to BMI and body shape were estimated using unconditional logistic regression models. The adjusted results indicated that ESCC risk in adults rapidly rose as height increased, plateauing at 170 cm among men and 157 cm among women. Among participants who were underweight, normal weight, or thinner than body shape 4, body weight loss was associated with increased risk of ESCC, and body weight gain was associated with decreased incidence of ESCC (ORs ranging from 0.40 to 0.76). Notably, however, changes in body weight did not significantly affect ESCC risk among participants who were overweight, obese, or larger than body shape 3. Maintaining a fit body shape and a reasonable BMI is advisable and of vital importance to reduce the risk of ESCC, especially in high-risk areas.
Introduction Targeted therapies are based on specific gene alterations. Various specimen types have been used to determine gene alterations, however, no systemic comparisons have yet been made. Herein, we assessed alterations in selected cancer-associated genes across varying sample sites in lung cancer patients. Materials and Methods Targeted deep sequencing for 48 tumor-related genes was applied to 153 samples from 55 lung cancer patients obtained from six sources: Formalin-fixed paraffin-embedded (FFPE) tumor tissues, pleural effusion supernatant (PES) and pleural effusion cell sediments (PEC), white blood cells (WBCs), oral epithelial cells (OECs), and plasma. Results Mutations were detected in 96% (53/55) of the patients and in 83% (40/48) of the selected genes. Each sample type exhibited a characteristic mutational pattern. As anticipated, TP53 was the most affected sequence (54.5% patients), however this was followed by NOTCH1 (36%, across all sample types). EGFR was altered in patient samples at a frequency of 32.7% and KRAS 10.9%. This high EGFR/ low KRAS frequency is in accordance with other TCGA cohorts of Asian origin but differs from the Caucasian population where KRAS is the more dominant mutation. Additionally, 66% (31/47) of PEC samples had copy number variants (CNVs) in at least one gene. Unlike the concurrent loss and gain in most genes, herein NOTCH1 loss was identified in 21% patients, with no gain observed. Based on the relative prevalence of mutations and CNVs, we divided lung cancer patients into SNV-dominated, CNV-dominated, and codominated groups. Conclusions Our results confirm previous reports that EGFR mutations are more prevalent than KRAS in Chinese lung cancer patients. NOTCH1 gene alterations are more common than previously reported and reveals a role of NOTCH1 modifications in tumor metastasis. Furthermore, genetic material from malignant pleural effusion cell sediments may be a noninvasive manner to identify CNV and participate in treatment decisions.
Previous studies have shown that single-nucleotide polymorphisms (SNPs) of a disintegrin and metalloproteinase with thrombospondin type 1 motif 4 (ADAMTS4) may involve in the pathogenesis of some diseases. However, it is not clear whether they are associated with hepatocellular carcinoma (HCC). A hospital-based case-control study, including 862 cases with HCC and 1120 controls, was conducted to assess the effects of 258 SNPs in the coding regions of ADAMTS4 on HCC risk and prognosis. We found that six SNPs in ADAMTS4 were differential distribution between cases and controls via the primary screening analyses; however, only rs538321148 and rs1014509103 polymorphisms were further identified to modify the risk of HCC (odds ratio: 2.73 and 2.95; 95% confidence interval, 2.28-3.29 and 2.43-3.58; P-value, 5.73 x 10(-27) and 1.36 x 10(-27), respectively). Significant interaction between these two SNPs and two known causes of hepatitis B virus and aflatoxin B1 were also observed. Furthermore, rs538321148 and rs1014509103 polymorphisms were associated not only with clinicopathological features of tumor such as tumor stage and grade, microvessel density, and vessel metastasis, but with poor overall survival. Additionally, these SNPs significantly downregulated ADATMS4 expression in tumor tissues. These data suggest that SNPs in the coding region of ADAMTS4, such as rs538321148 and rs1014509103, may be potential biomarkers for predicting HCC risk and prognosis.
Objective There is limited information from population-based cancer registries regarding prognostic features of bilateral primary breast cancer (BPBC). Methods Female patients diagnosed with BPBC between 2004 and 2014 were randomly divided into training (n = 7740) and validation (n = 2579) cohorts from the Surveillance, Epidemiology, and End Results Database. We proposed five various models. Multivariate Cox hazard regression and competing risk analysis were to explore prognosis factors in training cohort. Competing risk nomograms were constructed to combine significant prognostic factors to predict the 3-year and the 5-year survival of patients with BPBC. At last, in the validation cohort, the new score performance was evaluated with respect to the area under curve, concordance index, net reclassification index and calibration curve. Results We found out that age, interval time, lymph nodes invasion, tumor size, tumor grade and estrogen receptor status were independent prognostic factors in both multivariate Cox hazard regression analysis and competing risk analysis. Concordance index in the model of the worse characteristics was 0.816 (95% CI: 0.791-0.840), of the bilateral tumors was 0.819 (95% CI: 0.793-0.844), of the worse tumor was 0.807 (0.782-0.832), of the first tumor was 0.744 (0.728-0.763) and of the second tumor was 0.778 (0.762-0.794). Net reclassification index of the 3-year and the 5-year between them was 2.7% and -1.0%. The calibration curves showed high concordance between the nomogram prediction and actual observation. Conclusion The prognosis of BPBC depended on bilateral tumors. The competing risk nomogram of the model of the worse characteristics may help clinicians predict survival simply and effectively. Metachronous bilateral breast cancer presented poorer survival than synchronous bilateral breast cancer.
Adrenergic receptors (ARs) have gained attention for their involvement in breast cancer (BC) progression. Dexmedetomidine, a selective alpha(2)-AR agonist, has been reported to increase the malignancy of BC cells in vitro or stimulate tumor growth in mice. However, clinical evidence is lacking. Clinical research in this area is important as dexmedetomidine is widely used in BC surgery patients. Here we allocated 24 women with primary BC to the dexmedetomidine group (who received a total dose of 2 mu g kg(-1) dexmedetomidine perioperatively) or to the control group (who received the same volume of normal saline). Venous blood was obtained from all patients immediately upon entering the operating room and 24 hours postoperatively. Serum was then exposed to MCF-7 cells at a concentration of 10% for 24 hours. Cell proliferation, migration, and invasion were analyzed using EdU, Transwell, and Matrigel methods, respectively. We found that postoperative serum from those who received dexmedetomidine was associated with significantly increased cell proliferation, migration, and invasion compared with preoperative serum when used to culture MCF-7 cells. The mean percentage change from post to preoperative values in these cell functions was significantly larger in the dexmedetomidine group than in the control group (proliferation, 30.44% vs 8.45%, P = .0024; migration, 15.90% vs 3.25%, P = .0015; invasion, 8.17% vs 2.13%, P = .04). In conclusion, these findings suggest that in patients undergoing surgery for primary BC, perioperative administration of dexmedetomidine might influence the serum milieu in a way that favors the malignancy of MCF-7 cells. Clinical trial registration: NCT03108937.
Background Long noncoding RNAs (lncRNAs) are reported to play important roles in tumorigenesis of various malignant tumors. However, the clinical significance of aberrant lncRNA expression in hepatocellular carcinoma (HCC) is still elusive. Methods Firstly, a differentially expressed lncRNA CTC-297N7.9 in HCC was detected by analyzing the data from The Cancer Genome Atlas (TCGA). Secondly, the expression level of CTC-297N7.9 was examined in four HCC cell lines and 60 pairs of HCC tissues by polymerase chain reaction (PCR) assay at our center. Thirdly, receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic value of CTC-297N7.9 for HCC. Correlation and survival analysis of HCC patients from the TCGA and our center were also carried out to assess the predictive value of CTC-297N7.9. Finally, survival prognostic models were established combining lncRNA expression and other clinical parameters. Results The expression of CTC-297N7.9 was downregulated in HCC cell lines and HCC tissues. ROC curve revealed its significant diagnostic value in HCC. CTC-297N7.9 expression correlated with serum alpha-fetal protein (AFP), tumor stage, and tumor differentiation. Survival analysis indicated that overall survival (OS) and disease-free survival (DFS) are all positively associated with CTC-297N7.9 expression, especially in patients without viral hepatitis or cirrhosis. Cox regression analysis showed that CTC-297N7.9 expression level is an independent prognostic factor for both OS and DFS in HCC patients. Based on the model, CTC-297N7.9 was observed to be negatively correlated to risk score, indicating its role as a protective factor for HCC. Conclusion Our study demonstrated that the low expression of CTC-297N7.9 is associated with poor prognosis in HCC patients, suggesting its possible role as a potential prognostic marker for HCC.
Background Increasing evidence has validated the crucial role of alternative splicing (AS) in tumors. However, comprehensive investigations on the entirety of AS and their clinical value in glioblastoma (GBM) are lacking. Methods The AS profiles and clinical survival data related to GBM were obtained from The Cancer Genome Atlas database. Univariate and multivariate Cox regression analyses were performed to identify survival-associated AS events. A risk score was calculated, and prognostic signatures were constructed using seven different types of independent prognostic AS events, respectively. The Kaplan-Meier estimator was used to display the survival of GBM patients. The receiver operating characteristic curve was applied to compare the predictive efficacy of each prognostic signature. Enrichment analysis and protein interactive networks were conducted using the gene symbols of the AS events to investigate important processes in GBM. A splicing network between splicing factors and AS events was constructed to display the potential regulatory mechanism in GBM. Results A total of 2355 survival-associated AS events were identified. The splicing prognostic model revealed that patients in the high-risk group have worse survival rates than those in the low-risk group. The predictive efficacy of each prognostic model showed satisfactory performance; among these, the Alternate Terminator (AT) model showed the best performance at an area under the curve (AUC) of 0.906. Enrichment analysis uncovered that autophagy was the most enriched process of prognostic AS gene symbols in GBM. The protein network revealed that UBC, VHL, KCTD7, FBXL19, RNF7, and UBE2N were the core genes in GBM. The splicing network showed complex regulatory correlations, among which ELAVL2 and SYNE1_AT_78181 were the most correlated (r = -.506). Conclusions Applying the prognostic signatures constructed by independent AS events shows promise for predicting the survival of GBM patients. A splicing regulatory network might be the potential splicing mechanism in GBM.
Isolation of viable circulating tumor cells (CTC) holds the promise for improving screening, early diagnosis, and personalized treatment of lymphoma. In this study, we isolated and characterized spontaneously immortalized B-lymphocyte (SIBC) lines from HIV-infected patients with and without Non-Hodgkin's Lymphoma (AIDS-NHL). A total of 22 SIBC lines was isolated from peripheral blood mononuclear cells (PBMC) of HIV-infected patients with (n = 40) and without (n = 77) clinically detectable NHL, but not from healthy individuals (n = 34). Of these, 8 SIBC lines named HIV-SIBC were generated from HIV-infected patients without AIDS-NHL (10%, 8/77), while 14 SIBCs named AIDS-NHL-SIBC were from 13 of the AIDS-NHL patients (32.5%, 13/40). Among the 14 AIDS-NHL-SIBCs, 12 were derived from AIDS-NHL patients with poor prognoses (survival time less than 1 year). SIBCs displayed markers typical of memory B cells (CD3(-)CD20(+)CD27(+)) with EBV infection. Moreover, AIDS-NHL-SIBCs were representative of CTC as evidenced by monoclonal Ig gene rearrangement, abnormal chromosomal karyotype, and the formation of xenograft tumors, while HIV-SIBCs generated harbored some features of tumor cells, none had the capacity of xenograft tumor formation, suggesting HIV-SIBC present the precursor of CTC. These results indicate that SIBCs is associated with poor prognosis in AIDS-NHL patients and can be isolated from HIV-infected patients with NHL and without NHL. This findings point to the need for further molecular characterization and functional studies of SIBCs, which may prove the value of SIBCs in the diagnosis, prognoses, and screening for NHL among HIV-infected patients.
BRCA1, a multifunctional protein with an important role in DNA double-strand break repair by homologous recombination (HR), is subjected to ubiquitin-dependent degradation. To date, several E3 ubiquitin ligases have been identified to govern BRCA1 stability, but the deubiquitinase that counteracts its turnover remains undefined. In this study, we report that the ubiquitin-specific protease 9X (USP9X) is a bona fide deubiquitinase for BRCA1 in human cancer cells. Reciprocal immunoprecipitation assays demonstrated that USP9X interacted with BRCA1. Depletion of USP9X by short interfering RNAs or inhibition of USP9X by the small-molecular inhibitor WP1130 significantly reduced BRCA1 protein abundance, without affecting its mRNA levels. In contrast, overexpression of wild-type USP9X, but not its deubiquitinase activity-defective mutant (C1566S), resulted in an upregulation of BRCA1 protein levels. Moreover, USP9X depletion reduced the half-life of BRCA1, accompanied by an increase in its ubiquitination. HR assays showed that knockdown of USP9X significantly reduced HR efficiency, which was partially rescued by reintroduction of BRCA1 into USP9X-depleted cells. In support of these findings, USP9X knockdown significantly enhanced sensitivity to PARP inhibitor Olaparib and methyl methanesulfonate (MMS). Collectively, these results establish USP9X as a deubiquitinase for BRCA1 and reveal a previously unrecognized role of USP9X in the regulation of HR repair and the sensitivity of cancer cells to DNA-damaging agents.
Two genomewide association studies on pancreatic cancer have identified a novel single-nucleotide polymorphism of rs9564966 G > A on 13q22.1 region. However, the associations between the rs9564966 G > A polymorphism and the survival of Chinese patients with gastric cancer (GC) were unknown. In our present investigation, we adopted the Kaplan-Meier plots, Cox regression analyses, and the log-rank tests to explore the associations between rs9564966 G > A polymorphism and the prognosis of 911 Chinese patients with GC. Our results revealed that, compared with GG genotype, patients with GA + AA genotypes had poorer outcomes (HR = 1.348, 95% CI = 1.084-1.675, P = 0.007), especially in the subgroups of age <= 60 years, male, nondrinker, tumor size >5 cm, tumor site in Noncardia, intestinal-type tumor, T3/T4 level depth of invasion, N1/N2/N3 level lymph node metastasis, no distant metastasis, III/IV level TNM stages, and no chemotherapy. Our findings suggested that the rs9564966 G > A polymorphism may be a potential biomarker to predict the survival of Chinese patients with GC.
Triple-negative breast cancer (TNBC) is a heterogeneous disease with poorer prognosis than other subtypes, yet effective therapies are still not available. We aimed to compare the efficacy of various targeted therapies with chemotherapy (CT) in TNBC patients using a network meta-analysis. A systematic literature search was performed in PubMed, EMBASE, and the Cochrane Library. A total of 27 randomized controlled trials (RCTs), involving 6924 TNBC patients, were included. Olaparib significantly improved PFS (0.43, 0.29-0.64) and ORR (2.57, 1.31-5.09) in comparison with CT. As for bevacizumab + CT, it showed a significant improvement of PFS (0.66, 0.55-0.80) and ORR (2.15, 1.16-4.05) compared with CT + placebo. It was also superior to CT alone in PFS (0.48, 0.35-0.65) and pCR (1.30, 1.13-1.49 for breast and axillary nodes and 1.26, 1.11-1.44 for breast). Other targeted agents like iniparib, sorafenib, cetuximab, and ipatasertib combined with CT showed significant superiority in PFS compared with CT alone, and the HRs were 0.75 (0.62-0.90), 0.44 (0.21-0.91), 0.67 (0.47-0.96), and 0.44 (0.24-0.81), respectively, while some other agents such as sunitinib and cetuximab had the lowest SUCRA in OS, PFS, or ORR without any benefits. In conclusion, our results indicated that the addition of bevacizumab to CT was beneficial for TNBC patients, and olaparib had a great effect in PFS and ORR, especially for those with BRCA mutations. When combined with CT, targeted agents including iniparib, sorafenib, cetuximab, and ipatasertib may have better efficacies for treating TNBC.
TP53 mutation is considerably common in advanced high-grade serous ovarian cancer (HGSOC) and significantly associated with a poor prognosis. In this study, we investigated the role of Cyclin G1 (CCNG1), a target gene of wild-type TP53 (P53wt), in HGSOC and the possible regulatory mechanism between TP53 mutant (P53mt) and CCNG1 in the progression of HGSOC. High expression level of CCNG1 was found in 61.3% of HGSOC tissues and only 18.2% in fimbriae of fallopian tubes. Additionally, overexpression of CCNG1 was significantly associated with a shorter overall survival (P < 0.0001) and progression-free survival (P 0.0004) in HGSOC patients. In vitro, CCNG1 promoted both tumor cell motility by inducing epithelial-mesenchymal transition (EMT) and resistance to cisplatin (CDDP). In vivo, knockdown expression of CCNG1 inhibited cancer metastasis. Furthermore, P53mt increased the expression of CCNG1 by regulating Notch3 expression, and a positive correlation between CCNG1 and Notch3 protein expression was observed by Immunohistochemistry (IHC) (r = 0.39, P: 0.01528). In conclusion, the activation of P53mt-Notch3-CCNG1 pathway was responsible for tumor progression to advanced disease with correlation with worse prognosis in patients with HGSOC. These data suggest a possible molecular mechanism of disease and highlights CCNG1's potential role as a therapeutic target in HGSOC.
Background Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis. Complex genetic and epigenetic alterations are the two primary causes of HCC. The aim of the study was mainly to explore the correlation between the methylation status of DNAH17 and HCC. Methods We evaluated the methylation levels of DNAH17 in 163 HCC samples and their paired normal tissue using Sequenom EpiTYPER assays and performed the TaqMan copy number assay to assess the copy number status of DNAH17 in HCC samples. Results The mean methylation levels were significantly decreased in the tumor tissues compared to the paired normal tissues in both selected regions of DNAH17 (amplicon 1:58.7% vs 84.5%, P < 0.0001; amplicon 2:69.9% vs 84.5%, P = 0.0060). Contrarily?both RNA-seq and immunohistochemistry indicated the expression of DNAH17 was increased in tumor tissues (P < 0.05). DNMT inhibitor decitabine treatment could increase the expression of DNAH17 in HCC cell lines. DNAH17 gene amplification always companied with hypomethylation status. Moreover, hypomethylation status was associated with several clinical characteristics, such as male patients, higher AFP values, higher age of onset, fibrous capsules, tumor necrosis, liver cirrhosis, and tumor thrombus (P < 0.05). Receiver operator characteristic (ROC) curve analysis demonstrated the methylation levels of DNAH17 could efficiently predict the existence of the fibrous capsule (AUC = 0.695) and tumor thrombus (AUC = 0.806). Conclusions These findings suggested that aberrant methylation of DNAH17 was associated with comprehensive HCC clinicopathological factors and could be a promising biomarker for tumor thrombosis in HCC patients.
The kidney renal papillary cell carcinoma (KIRP) is a relatively rare type of kidney cancer. There has been no investigation to find a robust signature to predict the survival outcome of KIRP patients in the aspect of tumor immunology. In this study, 285 KIRP samples from The Cancer Genome Atlas (TCGA) were randomly divided into training and testing set. A total of 1534 immune-related genes from The Immunology Database and Analysis Portal (ImmPort) were used as candidates to construct the signature. Using univariate Cox analysis, we evaluated the relationship between overall survival and immune-related genes expression and found 272 immune-related genes with predicting prognostic ability. In order to construct an efficient predictive model, the Cox proportional hazards model with an elastic-net penalty was used and identified 23 groups after 1000 iterations. As a result, 15-genes model showing more stable than other gene groups was chosen to construct our immune-related risk signature. In line with our expectations, the signature can independently predict the survival outcome of KIRP patients. Patients with high-immune risk were found correlated with advanced stage. We also found that the high-immune risk patients with higher PBRM1 and SETD2 mutations, increasing chromosomal instability, together with the gene set enrichment analysis (GSEA) results showing intensive connection of our signature with immune pathways. In conclusion, our study constructs a robust 15-gene signature for predicting KIRP patients' survival outcome on the basis of tumor immune environment and may provide possible relationship between prognosis and immune-related biological function.