MicroRNAs (miRNAs) and Smad3, as key transcription factors in transforming growth factor-β1 (TGF-β1) signaling, help regulate various physiological and pathological processes. We investigated the roles of Smad3-regulated miRNAs with respect to lung adenocarcinoma cell apoptosis, proliferation, and metastasis. We observed that Smad3 and phospho-SMAD3 (p-Smad3) were decreased in miR-206- (or miR-140)-treated cells and there might be a feedback loop between miR-206 (or miR-140) and TGF-β1 expression. Smad3-related miRNAs affected tribbles homolog 2 (TRIB2) expression by regulating trib2 promoter activity through the CAGACA box. MiR-206 and miR-140 inhibited lung adenocarcinoma cell proliferation in vitro and in vivo by suppressing p-Smad3/Smad3 and TRIB2. Moreover, lung adenocarcinoma data supported a suppressive role for miR-206/miR-140 and an oncogenic role for TRIB2—patients with higher TRIB2 levels had poorer survival. In summary, miR-206 and miR-140, as tumor suppressors, induced lung adenocarcinoma cell death and inhibited cell proliferation by modifying oncogenic TRIB2 promoter activity through p-Smad3. MiR-206 and miR-140 also suppressed lung adenocarcinoma cell metastasis in vitro and in vivo by regulating EMT-related factors.
The results indicate that this proposed method can be a promising approach to improve the performance of the BCI system and can be an efficient method in daily application.
a b s t r a c tMicroRNAs have tumor suppressive or oncogenic roles in carcinogenesis. This study aimed to investigate the mechanism of let-7c in suppressing lung cancer cell proliferation. First, let-7c was revealed to be able to inhibit lung adenocarcinoma cell proliferation significantly. TRIB2 was further demonstrated to be a novel target and negatively regulated by let-7c. As downstream signals of TRIB2, the activities of C/EBP-a and phosphorylated p38MAPK were increased obviously in let-7c-treated cells compared with controls. Our results demonstrate that, through regulating the expression of TRIB2 and its downstream factors, let-7c can effectively inhibit A549 cell proliferation in vitro and in vivo.
Endometrial cancer (EC) is a common form of cancer in women. Metastasis is the main cause of EC treatment failure. Eukaryotic translation initiation factor 4E (eIF4E) is an oncogene that is overexpressed in a variety of malignancies and their distant metastases. The present study analyzed microarray data from the Oncomine database and revealed that high eIF4E expression was associated with poor prognosis and high pathological grade of EC. The expression of eIF4E was higher in EC tissues compared with in adjacent normal tissues. In addition, microRNA (miR)-320a and miR-340-5p expression levels were downregulated in EC tissues compared with those in adjacent normal tissues, which suggested that these microRNAs may serve as EC tumor suppressor genes. miR-320a and miR-340-5p could bind to the 3'-UTR of eIF4E mRNA, thus downregulating the expression of eIF4E and phosphorylated (p)-eIF4E in EC cells. Overexpression of miR-320a or miR-340-5p effectively suppressed HEC-1A cell migration and invasion. The downregulation of eIF4E and p-eIF4E following miR-320a or miR-340-5p transfection reduced the invasiveness and metastatic capability of EC cells in a manner associated with decreased expression of matrix metallopeptidase (MMP)-3 and MMP-9. In addition, one of the effects of transforming growth factor β1 (TGF-β1), which is to induce the phosphorylation of eIF4E, was suppressed by miR-320a and miR-340-5p overexpression. These two microRNAs also attenuated the features of TGF-β1-induced epithelial-mesenchymal transition (EMT). In conclusion, the results of the present study demonstrated that eIF4E was upregulated in EC, whereas miR-320a and miR-340-5p were downregulated in EC compared with adjacent normal tissues. In vitro, miR-320a and miR-340-5p inhibited the migratory capability of EC cells by downregulating MMP-3 and MMP-9 and prevented TGF-β1-induced EMT through p-eIF4E.
Circulating microRNAs (miRNAs) are important in the diagnosis of a number of diseases, since serum or plasma miRNAs are more stable compared with miRNA isolated from blood samples. The aim of the present study was to investigate the association between the expression levels of serum let-7c miRNA and the clinical diagnosis of breast cancer (BC). The circulating let-7c levels of 90 BC patients and 64 healthy controls were determined by performing a reverse transcription-quantitative polymerase chain reaction assay. The results demonstrated that let-7c expression was downregulated in the BC tissues compared with the paracarcinoma control tissues. In addition, the let-7c expression in the serum of BC patients was significantly lower compared with the healthy controls (P<0.01). Using a cutoff value of 0.374×103 copies/ml, the serum expression levels of let-7c exhibited 87.5% sensitivity and 78.9% specificity for distinguishing BC patients from healthy controls (area under the receiver operating characteristic curve, 0.848; 95% confidence interval, 0.785–0.911). Furthermore, the results demonstrated that the serum expression levels of let-7c were significantly higher in premenopausal compared with postmenopausal patients (P<0.05), supporting the hypothesis that postmenopausal status may affect the serum expression levels of let-7c. However, no statistically significant differences were detected in the serum levels of let-7c between ER (or PR)-positive and -negative patients. Therefore, the current study hypothesized that serum let-7c may be used as a novel and valuable biomarker for the diagnosis of BC.
Objective: Germline alterations in the breast cancer susceptibility genes type 1 and 2, BRCA1 and BRCA2, predispose individuals to hereditary cancers, including breast, ovarian, prostate, pancreatic, and stomach cancers. Accumulating evidence suggests inherited genetic susceptibility to lung cancer. The present study aimed to survey the prevalence of pathogenic germline BRCA mutations (gBRCAm) and explore the potential association between gBRCAm and disease onset in Chinese advanced non-small cell lung cancer (NSCLC) patients. Methods: A total of 6,220 NSCLC patients were screened using capture-based ultra-deep targeted sequencing to identify patients harboring germline BRCA1/2 mutations. Results: Out of the 6,220 patients screened, 1.03% (64/6,220) of the patients harbored the pathogenic gBRCAm, with BRCA2 mutations being the most predominant mutations (49/64, 76.5%). Patients who developed NSCLC before 50 years of age were more likely to carry gBRCAm (P = 0.036). Among the patients harboring classic lung cancer driver mutations, those with concurrent gBRCAm were significantly younger than those harboring the wild-type gBRCA (P = 0.029). By contrast, the age of patients with or without concurrent gBRCAm was comparable to those of patients without the driver mutations (P = 0.972). In addition, we identified EGFR-mutant patients with concurrent gBRCAm who showed comparable progression-free survival but significantly longer overall survival (P = 0.002) compared to EGFR-mutant patients with wild-type germline BRCA. Conclusions: Overall, our study is the largest survey of the prevalence of pathogenic gBRCAm in advanced Chinese NSCLC patients. Results suggested a lack of association between germline BRCA status and treatment outcome of EGFR-TKI. In addition, results showed a positive correlation between pathogenic gBRCAm and an early onset of NSCLC.
Background: Immune checkpoint inhibitors (ICIs) prolong overall survival (OS) in patients with advanced lung squamous cell carcinoma (LUSC). However, predictive and prognostic factors related to ICIs in LUSC remain elusive. This study aimed to identify predictors that are related to better clinical benefit and outcomes in LUSC patients treated with immunotherapy.Methods: Capture-based targeted sequencing was performed in 64 patients with advanced LUSC who underwent immunotherapy. Tumor mutational burden (TMB) was defined as the sum of nonsynonymous single nucleotide and indel variants. Programmed cell death ligand-1 (PD-L1) expression was evaluated by immunohistochemical analysis. Clinicopathological characteristics including age, sex, performance status, smoking history, body mass index (BMI), blood fat, brain metastases, liver metastases, previous thoracic radiotherapy, and treatment lines were analyzed.Results: The most commonly mutated genes included TP53, CDKN2A, KEAP1, CREBBP, KRAS, BIM, AMER1, and APC. Copy number variations most frequently occurred in AR, SOX2, PIK3CA, EGFR, RICTOR, FGFR1, and ZNF703. The median and mean TMB was 9.35 and 10.62 mutations per megabase, respectively. Positive PD-L1 expression was detected in 29.7% patients. Patients with a history of heavy smoking (≥ 40 pack-years) were more likely to have positive PD-L1 expression (35% vs. 16.7%, P=0.04) and higher TMB (11.1 vs. 9.8 mut/Mb, P=0.04). Gene alterations had no impact on PD-L1 expression or TMB level. The median progression-free survival (PFS) was 6.7 months and median OS was 13.7 months. Higher TMB was independently associated with longer PFS (P=0.01) and OS (P=0.02), and this correlation was more pronounced in patients treated with ICIs as a single agent (P=0.0001). Higher TMB was also associated with better disease control rate (DCR) (P=0.02). Compared with wild-type, patients with KRAS mutation and EGFR amplification had higher objective response rates (ORR, P=0.01). Conclusions:The predictive value of TMB is more significant in LUSC patients receiving ICI as a single agent than as a combination therapy. The combination of Eastern Cooperative Oncology Group performance status (ECOG-PS), smoking status, TMB, PD-L1, and genomic variation might be helpful for personalized immunotherapy decisions in clinical practice for advanced LUSC.
Short-chain fatty acid (SCFA) plays an important role in improving obesity and related metabolic syndrome induced by high-fat diet. We used the prepared inulin propionate ester (IPE) as a system for the targeted release of propionate to the colon to elucidate the role of IPE in regulating obesity and metabolic syndrome, and intestinal microbial homeostasis, in diet-induced obese mice. With this strategy, IPE significantly increased the SCFA contents in the colon and resulted in significant body weight reduction, insulin resistance amelioration, and gastrointestinal hormone (glucagon-like peptide and peptide YY) secretion (P < 0.05). The IPE intervention reduced liver fatty accumulation, which improved obesity-related fatty liver disease (P < 0.05). IPE supplementation increased the richness and diversity of the microbial community and altered bacterial population at both the phylum and family level. Intestinal microbial results showed that the relative abundance of Desulfovibrionaceae and Erysipelotrichaceae, which promote the production of inflammatory factors, was reduced. Our results demonstrate that IPE can be used as an effective strategy for delivering propionate to obese mice colon, which can ameliorate obesity and associated metabolic syndrome and modify intestinal microbial homeostasis.
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