MiR-135b improves proliferation and regulates chemotherapy resistance in ovarian cancer.

MicroRNAs act as regulators in ovarian tumorigenesis and progression by involving different molecular pathways. Here, we examined the role of miR-135b on growth, chemotherapy resistance in OVCAR3 and SKOV3 ovarian cancer cells. MTT assay was performed to examine proliferation. Transwell migration and matrigel invasion assays were used to assess migration and invasion. Caspase-Glo3/7 assay was carried out to evaluate apoptosis. The dual-luciferase reporter assay was performed to validate the putative binding site. Meanwhile, the miR-135b levels in human ovarian cancer tissue were detected by qPCR assay. Overexpression of miR-135b increased growth, and improved migration and invasion in ovarian cancer cells. Meanwhile, overexpression of miR-135b decreased the cisplatin treatment sensitivity in OVCAR3 and SKOV3 cells. The cisplatin-induced apoptosis was decreased by miR-135b. Furthermore, miR-135b could alter epithelial to mesenchymal transition (EMT) associated proteins expression including E-cadherin, N-cadherin, snail and Vimentin in ovarian cancer cells. Further study demonstrated aberrant expression of miR-135b regulated PTEN and p-AKT expression in ovarian cancer cells. The expression level of miR-135b was increased in human ovarian cancer tissue, compared with normal ovary tissue. MiR-135b involves in tumorigenesis and progression in ovarian cancer cells, and might serve as a promising biomarker to predict chemotherapy sensitivity and prognosis in ovarian cancer.

Extracellular vesicle biomarkers for pancreatic cancer diagnosis: a systematic review and meta-analysis.

BACKGROUND: Extracellular vesicle (EV) biomarkers have promising diagnosis and screening capacity for several cancers, but the diagnostic value for pancreatic cancer (PC) is controversial. The aim of our study was to review the diagnostic performance of EV biomarkers for PC. METHODS: We performed a systematic review of PubMed, Medline, and Web Of Science databases from inception to 18 Feb 2022. We identified studies reporting the diagnostic performance of EV biomarkers for PC and summarized the information of sensitivity, specificity, area under the curve (AUC), or receiver operator characteristic (ROC) curve) in according to a pre-designed data collection form. Pooled sensitivity and specificity was calculated using a random-effect model. RESULTS: We identified 39 studies, including 2037 PC patients and 1632 noncancerous, seven of which were conducted independent validation tests. Seventeen studies emphasized on EV RNAs, sixteen on EV proteins, and sixteen on biomarker panels. MiR-10b, miR-21, and GPC1 were the most frequently reported RNA and protein for PC diagnosis. For individual RNAs and proteins, the pooled sensitivity and specificity were 79% (95% CI: 77-81%) and 87% (95% CI: 85-89%), 72% (95% CI: 69-74%) and 77% (95% CI: 74-80%), respectively. the pooled sensitivity and specificity of EV RNA combined with protein panels were 84% (95% CI: 81-86%) and 89% (95% CI: 86-91%), respectively. Surprisingly, for early stage (stage I and II) PC EV biomarkers showed excellent diagnostic performance with the sensitivity of 90% (95% CI: 87-93%) and the specificity of 94% (95% CI: 92-95%). Both in sensitivity and subgroup analyses, we did not observe notable difference in pooled sensitivity and specificity. Studies might be limited by the isolation and detection techniques of EVs to a certain extent. CONCLUSIONS: EV biomarkers showed appealing diagnostic preference for PC, especially for early stage PC. Solving the deficiency of technologies of isolation and detection EVs has important implications for application these novel noninvasive biomarkers in clinical practice.

The Apparent Diffusion Coefficient of Diffusion-Weighted Whole-Body Magnetic Resonance Imaging Affects the Survival of Multiple Myeloma Independently.

Background: Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used to evaluate bone diseases of multiple myeloma (MM), but there is lack of quantitative indicator for DW-MRI to reflect the prognosis of MM. Apparent diffusion coefficient (ADC) values in DW-MRI has potential correlations between some indexes of MM, but the influence of ADC on MM survival needs to be further verified. Methods: A total of 381 newly diagnosed MM patients were enrolled in the study to analyze the effect of ADC values in DW-MRI on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method was used to perform univariate survival analysis, and the Cox proportional hazards model was used for multivariate analysis. In addition to the ADC value, genetic and serological indexes were also included. Results: The survivals were observed in univariate ADC stratification with median PFS of 52.0, 45.0, 34.0, and 26.0 months (the unit of ADC value was 10-3 mm2/s; the ADC ranges were ADC < 0.4886, 0.4886 ≤ ADC < 0.6545, 0.6545 ≤ ADC < 0.7750, and ADC ≥ 0.7750; 95% CI, 43.759-62.241, 46.336-53.664, 39.753-46.247, and 27.812-32.188). The OS were 81.0, 61.0, 47.0, and 36.0 months (p < 0.001; 95% CI, 71.356-82.644, 67.630-70.370, 57.031-60.969, and 36.107-43.893). In Cox proportional hazards model, the ADC value was considered to be an independent risk factor affecting PFS and OS of MM (both p < 0.001). Conclusions: This study supports that ADC in DW-MRI may independently stratify MM patients and better predict their prognosis. The combined use of DW-MRI and other parameters allows more accurate evaluation of MM survival. Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=49012, ChiCTR2000029587.

Role of whole-body diffusion-weighted imaging in evaluation of multiple myeloma.

ABSTRACT: The evaluation of bone disease in multiple myeloma (MM) is an important topic in imaging. This study retrospectively investigated whole-body diffusion-weighted imaging (WB-DWI) in the evaluation of bone marrow infiltration and treatment response in MM.A total of 126 patients with MM who underwent WB-DWI between January 2016 and December 2020 were enrolled. All the patients received 4-course induction chemotherapy. WB-DWI was performed before and after chemotherapy to measure the apparent diffusion coefficient (ADC) values. According to gender and Revised International Staging System (RISS) staging groups, the relationship between ADC value and bone marrow plasma cell infiltration ratio before treatment were explored using Spearman and Pearson correlation coefficients. Comparison of ADC values before and after treatment according to different chemotherapy regimens and treatment response was performed by 2-independent samples non-parametric tests and t test.There was a negative correlation between the ADC value and the degree of bone marrow infiltration and this was statistically significant (r = -0.843, P < .001). In different gender and RISS groups, ADC value before treatment was negatively correlated with the proportion of plasma cell infiltration (male, r = -0.849; female, r = -0.836; Stage I, r = -0.659; Stage II, r = -0.870; Stage III, r = -0.745; all P < .001). The ADC values of all subjects increased to varying degrees after 4-course induction chemotherapy, including different chemotherapy regimens and treatment responses (all P < .05 except for progressive disease group).The ADC value was negatively correlated with the degree of bone marrow infiltration in different gender and RISS stages. The ADC value increased after treatment, but it was not consistent with progressive disease group. The increase of ADC value may indicate the disease burden and outcome of MM induced chemotherapy.

Prognostic value of microRNA-20b expression level in patients with prostate cancer.

BACKGROUND: miR-20b is a member of the miR-106a-363 gene cluster located in the mammalian X chromosome, the larger miR-17 family, and the miR-17-92 and miR-106b-25 gene clusters. Previous studies have indicated that miR-20b may function as oncogene or tumor suppressor in different types of cancers. The present study analyzed the association between miR-20b and clinicopathological characteristics of patients with prostate cancer. METHODS: A total of 127 pairs of prostate cancer tissue samples and adjacent prostate tissue samples were collected from April 2013 to March 2018. The associations between miR-20b expression levels and clinicopathological factors were assessed using the χ2­test. Survival was estimated using the Kaplan-Meier method, and the differences in survival according to miR-20b expression were compared using the log-rank test. Prognostic values of miR-20b expression and clinical outcomes were evaluated by Cox regression analysis. RESULTS: The relative expression of miR-20b in prostate cancer tissues was significantly higher than that in adjacent noncancerous prostate tissues (P<0.001). miR-20b expression was observed to be significantly associated with Gleason score (P<0.001), lymph node metastasis (P<0.001), and TNM stage (P=0.002). The log-rank test indicated that patients with increased miR-20b expression experienced poor overall survival (P=0.037). Multivariate Cox regression analysis showed that miR-20b expression level (HR=2.181, 95% CI: 1.772-9.021, P=0.016) was an independent factor in predicting the overall survival of prostate cancer patients. CONCLUSION: The present study demonstrated that tissue miR-20b expression level could be a promising biomarker of prognosis in prostate cancer.

MicroRNA-135a promotes proliferation, migration, invasion and induces chemoresistance of endometrial cancer cells.

AIMS: MicroRNAs play essential roles in tumorigenesis and progression in various cancers including endometrial cancer. Here we assessed the role of miR-135a on proliferation, chemosensitivity, migration and invasion of endometrial cancer cells. METHODS: WST-1 assay was performed to examine the proliferation of HEC-1-B and ISHIKAWA endometrial cancer cells with altered expression of miR-135a, with or without cisplatin treatment. Transwell migration and matrigel invasion assays were used to assess the migration and invasion of endometrial cancer cells. The Caspase-Glo3/7 assay was used to examine the effect of miR-135a on cisplatin-induced apoptosis of endometrial cancer cells. The dual-luciferase reporter assay was conducted to validate the putative binding site. RESULTS: Upregulation of miR-135a improved the proliferation, and promoted migration and invasion of endometrial cancer cells. Furthermore, miR-135a decreased the sensitivity of HEC-1-B and ISHIKAWA cells after cisplatin treatment. The cisplatin-induced apoptosis in endometrial cancer cells was inhibited by miR-135a by regulation of BAX and Bcl-2 expression. Meanwhile, miR-135a could regulate epithelial to mesenchymal transition (EMT) by altering the expression of E-cadherin, N-cadherin, snail and Vimentin in endometrial cancer cells. Further study showed that the expression levels of PTEN and p-AKT in endometrial cancer cells were changed after aberrant expression of miR-135a. CONCLUSION: MiR-135a played important roles in tumorigenesis and disease progression of endometrial cancer by regulating proliferation and chemosensitivy of endometrial cancer cells by targeting AKT signaling pathway. Our study indicates that miR-135a might act as a potential biomarker to predict chemotherapy response and prognosis in endometrial cancer.

lncRNA BCAR4 sponges miR­370­3p to promote bladder cancer progression via Wnt signaling.

Accumulating evidence suggests that the aberrant expression of long non­coding RNAs (lncRNAs) is involved in the initiation, development and metastasis of bladder cancer (BC). Although several differentially expressed lncRNAs have been identified via lncRNA expression profiling of BC tissues, their functions and the molecular mechanisms underlying these functions remain to be fully elucidated. In the present study, elevated levels of lncRNA breast cancer anti­estrogen receptor 4 (BCAR4) were identified in BC tissues compared with matched healthy tissues. Silencing of BCAR4 inhibited cell proliferation and induced apoptosis in BC cell lines 5637 and T24. Downregulation of BCAR4 led to the inactivation of Wnt signaling. Mechanistically, BCAR4 directly sponged microRNA (miR)­370­3p and elevated Wnt7a expression. Endogenous expression of Wnt7a reversed BCAR4 silencing­mediated cell growth arrest and induction of apoptosis in BC cells accompanied with a re­activation of Wnt signaling. Reverse transcription­quantitative PCR indicated that there was a strong association between BCAR4, miR­370­3p and Wnt7a expression in tumors from patients with BC compared with healthy control tissues. In conclusion, results of the present study suggest that lncRNA BCAR4 promoted proliferation and survival of BC cells via downregulation of miR­370­3p. Therefore, lncRNA BCAR4 may be a lncRNA of oncogenic potential in BC.

Circulating miR-17 as a promising diagnostic biomarker for lung adenocarcinoma: evidence from the Gene Expression Omnibus.

BACKGROUND: A definitive preoperative diagnosis of lung adenocarcinoma (LUAD) is a clinical challenge. Informative and blood-based microRNAs (miRNAs) may provide new insights on LUAD screening and detection but are limited by suboptimal accuracy. METHODS: The raw expression levels of circulating miR-21, miR-155, miR-210, miR-126, miR-182, and miR-17 in LUAD cases and healthy controls from the Gene Expression Omnibus (GEO) database were obtained and analyzed to identify accurate diagnostic miRNAs biomarkers for LUAD detection. We applied a meta-analysis to determine the magnitude of statistically significant miRNAs in LUAD samples, based on estimation outcomes acquired by analyzing raw data. Furthermore, bioinformatics analysis was conducted to reveal the function of significant miRNAs in the comprehensive underlying mechanisms of LUAD biology. RESULTS: A total of 5 raw microarray datasets, including 87 LUAD samples and 83 healthy controls, were eligible. Through our analysis, the primary outcome measure was that circulating miR-17 showed a favorable accuracy in diagnosing LUAD, and the overall pooled area under the curve (AUC) value was 0.79. Furthermore, a total of 85 predicted target genes were chosen, and 29 gene ontology (GO) items and 3 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways showed a significant statistical difference, which demonstrated that the target genes are involved in the biological processes of LUAD. A protein-protein interaction (PPI) network analysis revealed 10 hub genes, namely CCND2, E2F3, TNRC6B, AGO1, AAK1, RAB5B, LDLR, FBXO21, UBE3C, and MYLIP, located in the center of the PPI network. CONCLUSIONS: In conclusion, circulating miR-17 may be a quality diagnostic biomarker for LUAD screening, but confirmation by a large, rigorous clinical validation in a longitudinal setting is warranted.

MicroRNA-498 promotes proliferation, migration, and invasion of prostate cancer cells and decreases radiation sensitivity by targeting PTEN.

Prostate cancer (PCa) remains the secondary highest cause of cancer-related death in the United States in men. It has been reported that microRNAs can serve as key regulators in tumor development and progression in various cancers including PCa. In this study, we examined the effect of miR-498 on proliferation, radiosensitivity, invasion, and migration of PCa cells. The proliferation of LNCaP and DU-145 PCa cells with altered expression of miR-498 was evaluated by MTT assay. The invasion and migration of LNCaP and DU-145 PCa cells were assess by matrigel invasion assay and transwell migration assay. The protein expression level in PCa cells was examined by western blot. The function of miR-498 on radiation-induced apoptosis in LNCaP and DU-145 PCa cells was detected by Caspase-Glo3/7 assay. Forced expression of miR-498 improved the proliferation, invasion and migration in PCa cells. Furthermore, miR-498 decreased the sensitivity of PCa cells after ionizing radiation treatment. MiR-498 reduced the radiation-induced apoptosis in PCa cells by regulation of BAX and Bcl-2 expression. Meanwhile, miR-498 altered the expression of E-cadherin, N-cadherin, snail, and Vimentin in both LNCaP and DU-145 PCa cells and regulated epithelial to mesenchymal transition (EMT). Further study showed that aberrant expression of miR-498 changed the expression levels of phosphatase and tensin homolog and p-AKT in LNCaP and DU-145 PCa cells. In a summary, miR-498 displayed important roles in tumor development and progression in PCa cells, and might act as a potential prognostic biomarker and predict radiotherapy response in PCa.

Functional analysis of gene expression profiling-based prediction in bladder cancer.

The present study aimed to analyze the modification of gene expression in bladder cancer (BC) by identifying significant differentially expressed genes (DEGs) and functionally assess them using bioinformatics analysis. To achieve this, two microarray datasets, GSE24152 (which included 10 fresh tumor tissue samples from urothelial bladder carcinoma patients and 7 benign mucosa samples from the bladder), and GSE42089 (which included 10 tissues samples from urothelial cell carcinoma patients and 8 tissues samples from the normal bladder), were downloaded from the Gene Expression Omnibus database for further analysis. Differentially expressed genes (DEGs) were screened between benign the mucosa and control groups in GSE24152 and GSE42089 datasets. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analysis were performed on overlapping DEGs identified in GSE24152 and GSE42089. Protein-protein interaction (PPI) networks and sub-networks were then constructed to identify key genes and main pathways. GO terms analysis was also performed for the selected clusters. In total, 1,325 DEGs in GSE24152 and 647 DEGs in GSE42089 were screened, in which 619 common DEGs were identified. The DEGs were mainly enriched in pathways and GO terms associated with mitotic and chromosome assembly, including nucleosome assembly, spindle checkpoint and DNA replication. In the interaction network, progesterone receptor (PGR), MAF bZIP transcription factor G (MAFG), cell division cycle 6 (CDC6) and members of the minichromosome maintenance family (MCMs) were identified as key genes. Histones were also considered to be significant factors in BC. Nucleosome assembly and sequence-specific DNA binding were the most significant clustered GO terms. In conclusion, the DEGs, including PGR, MAFG, CDC6 and MCMs, and those encoding the core histone family were closely associated with the development of BC via pathways associated with mitotic and chromosome assembly.

Maternal Low-protein Diet Alters Ovarian Expression of Folliculogenic and Steroidogenic Genes and Their Regulatory MicroRNAs in Neonatal Piglets.

Maternal malnutrition during pregnancy may give rise to female offspring with disrupted ovary functions in adult age. Neonatal ovary development predisposes adult ovary function, yet the effect of maternal nutrition on the neonatal ovary has not been described. Therefore, here we show the impact of maternal protein restriction on the expression of folliculogenic and steroidogenic genes, their regulatory microRNAs and promoter DNA methylation in the ovary of neonatal piglets. Sows were fed either standard-protein (SP, 15% crude protein) or low-protein (LP, 7.5% crude protein) diets throughout gestation. Female piglets born to LP sows showed significantly decreased ovary weight relative to body weight (p<0.05) at birth, which was accompanied with an increased serum estradiol level (p<0.05). The LP piglets demonstrated higher ratio of bcl-2 associated X protein/B cell lymphoma/leukemia-2 mRNA (p<0.01), which was associated with up-regulated mRNA expression of bone morphogenic protein 4 (BMP4) (p<0.05) and proliferating cell nuclear antigen (PCNA) (p<0.05). The steroidogenic gene, cytochrome P450 aromatase (CYP19A1) was significantly down-regulated (p<0.05) in LP piglets. The alterations in ovarian gene expression were associated with a significant down-regulation of follicle-stimulating hormone receptor mRNA expression (p<0.05) in LP piglets. Moreover, three microRNAs, including miR-423-5p targeting both CYP19A1 and PCNA, miR-378 targeting CYP19A1 and miR-210 targeting BMP4, were significantly down-regulated (p<0.05) in the ovary of LP piglets. These results suggest that microRNAs are involved in mediating the effect of maternal protein restriction on ovarian function through regulating the expression of folliculogenic and steroidogenic genes in newborn piglets.

[B-type natriuretic peptides and subclinical target organ damage in essential hypertensive patients].

OBJECTIVE: To investigate the relationship between B-type natriuretic peptides (BNP) and subclinical target organ damage in essential hypertensive (EH) patients. METHODS: A total of 317 EH patients were divided into 3 groups according to BNP levels, namely normal (BNP<600 ng/L) group (n=102), moderate (600-883.5 ng/L) group (n=116), and elevated BNP (>883.5 ng/L) group (n=99). The blood pressure, left ventricular mass index (LVMI), the intima media thickness (IMT) of the common carotid artery, the plaque size in the coronary artery (CS) and microalbuminuria levels were analyzed in these patients. RESULTS: The EH patients with moderate and elevated BNP showed significantly higher LVMI, IMT, CS and microalbuminuria levels than those with normal BNP level (LVMI: 102.8∓23.12 and 123.9∓26.47 vs 91.09∓18.71 g/m2; IMT: 0.95∓0.32 and 1.16∓0.37 vs 0.84∓0.28 mm; microalbuminuria: 31.36∓20.55 and 36.73∓22.07 vs 23.21∓18.68, P<0.01). After adjustment, BNP was positively correlated to LVMI, IMT, CS and microalbuminuria level (r=0.45, 0.43, 0.39 and 0.41, respectively, P<0.01). Multivariate logistic regression analysis showed that age, systolic blood pressure, BNP, FPG, and microalbuminuria, LDL-C, and BMI were all related to the occurrence of subclinical target organ damages. CONCLUSION: BNP is positively correlated to subclinical target organs damages in EH patients.

[Effects of rosuvastatin on left ventricular cardiac function, arteriosclerotic plaque and high sensitive C-reactive protein in hypertensive patients with mild LDL-C elevation].

OBJECTIVE: To observe the effect of rosuvastatin on left ventricular cardiac function, arteriosclerotic plaque and high sensitive C-reactive protein (hs-CRP) in hypertensive patients with mild elevation of LDL-C. METHODS: Seventy-nine patients with a SBP of 140-179 mmHg and/or a DBP of 90-109 mmHg and mild elevated LDL-C were treated with rosuvastatin for 12 months (n=40) or not (n=39). The changes of hs-CRP, arteriosclerosis plaque and cardiac function at the end of the 12-months treatment relative to the baseline levels were analyzed. RESULTS: After 12 months of treatment, LDL-C was decreased by 33.2% in rosuvastatin group but remained unchanged in patients without rosuvastatin treatment. The left ventricular peak filling rate (LVPFR) increased significantly from 1.85 to 2.59 (P<0.05) and the serum levels of hs-CRP reduced significantly (P<0.05) after rosuvastatin treatment. The size of the plaques reduced significantly after a 12-month rosuvastatin therapy. CONCLUSION: Rosuvastatin therapy on the basis of conventional anti-hypertensive drugs can obviously improve the left ventricular diastolic function and produce favorable effects on arteriosclerotic plaques.