Biofilm Production Ability, Virulence and Antimicrobial Resistance Genes in Staphylococcus aureus from Various Veterinary Hospitals.

: Staphylococcus aureus (S. aureus) is one of the most clinically important zoonotic pathogens, but an understanding of the prevalence, biofilm formulation ability, virulence, and antimicrobial resistance genes of S. aureus from veterinary hospitals is lacking. By characterizing S. aureus in different origins of veterinary hospitals in Guangzhou, China, in 2019, we identified with the presence of S. aureus in pets (17.1%), veterinarians (31.7%), airborne dust (19.1%), environmental surfaces (4.3%), and medical device surfaces (10.8%). Multilocus sequence typing (MLST) and Staphylococcus protein A (spa) typing analyses demonstrated methicillin-sensitive S. aureus (MSSA) ST398-t571, MSSA ST188-t189, and methicillin-resistant S. aureus (MRSA) ST59-t437 were the most prevalent lineage. S. aureus with similar pulsed-field gel electrophoresis (PFGE) types distributed widely in different kinds of samples. The crystal violet straining assays revealed 100% (3/3) of MRSA ST59 and 81.8% (9/11) of MSSA ST188 showed strong biofilm formulation ability, whereas other STs (ST1, ST5, ST7, ST15, ST88, ST398, ST3154 and ST5353) showed weak biofilm production ability. Polymerase chain reaction (PCR) confirmed the most prevalent leucocidin, staphylococcal enterotoxins, ica operon, and adhesion genes were lukD-lukE (49.0%), sec-sel (15.7%), icaA-icaB-icaC-icaR (100.0%), and fnbB-cidA-fib-ebps-eno (100.0%), respectively. Our study showed that the isolates with strong biofilm production ability had a higher prevalence in clfA, clfB, fnbA and sdrC genes compared to the isolates with weak biofilm production ability. Furthermore, 2 ST1-MRSA isolates with tst gene and 1 ST88-MSSA isolate with lukS/F-PV gene were detected. In conclusion, the clonal dissemination of S. aureus of different origins in veterinary hospitals may have occurred; the biofilm production capacity of S. aureus is strongly correlated with ST types; some adhesion genes such as clfA, clfB, fnbA, and sdrC may pose an influence on biofilm production ability and the emergence of lukS/F-PV and tst genes in S. aureus from veterinary hospitals should raise our vigilance.

Long Noncoding RNA MALAT1 Contributes to Sorafenib Resistance by Targeting miR-140-5p/Aurora-A Signaling in Hepatocellular Carcinoma.

Long noncoding RNAs (lncRNA) have been found to play critical roles in tumorigenesis and the development of various cancers, including hepatocellular carcinoma (HCC). Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) has been identified as an oncogene and prognostic biomarker in HCC. Here, we demonstrated that MALAT1 expression was obviously high in sorafenib-resistant HCC cells. Furthermore, knockdown of MALAT1 increased sorafenib sensitivity in nonresponsive HCC cells, whereas forced expression of MALAT1 conferred sorafenib resistance to responsive HCC cells in vitro In addition, loss/gain-of-function assays revealed that MALAT1 promoted cell proliferation, migration, and epithelial-mesenchymal transition in HCC cells. Mechanistically, MALAT1 regulated Aurora-A expression by sponging miR-140-5p, thus promoting sorafenib resistance in HCC cells. Moreover, MALAT1 inhibition enhanced the antitumor efficacy of sorafenib in vivo Clinically, we found that MALAT1 expression was negatively correlated with miR-140-5p expression but positively correlated with Aurora-A expression in patients with HCC and that upregulated MALAT1 was closely correlated with poor survival outcomes in patients with HCC. These findings indicated that MALAT1 may be a novel target for prognosis prediction and therapeutic strategies in patients with HCC treated with sorafenib.

MicroRNA-145: a potent tumour suppressor that regulates multiple cellular pathways.

MicroRNAs are endogenous, small (18-25 nucleotides) non-coding RNAs, which regulate genes expression by directly binding to the 3'-untranslated regions of the target messenger RNAs. Emerging evidence shows that alteration of microRNAs is involved in cancer development. MicroRNA-145 is commonly down-regulated in many types of cancer, regulating various cellular processes, such as the cell cycle, proliferation, apoptosis and invasion, by targeting multiple oncogenes. This review aims to summarize the recent published literature on the role of microRNA-145 in regulating tumourigenesis and progression, and explore its potential for cancer diagnosis, prognosis and treatment.

HDAC 1/4-mediated silencing of microRNA-200b promotes chemoresistance in human lung adenocarcinoma cells.

Chemoresistance is one of the most significant obstacles in lung adenocarcinoma (LAD) treatment, and this process involves genetic and epigenetic dysregulation of chemoresistance-related genes. Previously, we have shown that restoration of microRNA (miR)-200b significantly reverses chemoresistance of human LAD cells by targeting E2F3. However, the molecular mechanisms involved in the silencing of miR-200b are still unclear. Here we showed that histone deacetylase (HDAC) inhibitors could restore the expression of miR-200b and reverse chemoresistant phenotypes of docetaxel-resistant LAD cells. HDAC1/4 repression significantly increased miR-200b expression by upregulating histone-H3 acetylation level at the two miR-200b promoters partially via a Sp1-dependent pathway. Furthermore, silencing of HDAC1/4 suppressed cell proliferation, promoted cell apoptosis, induced G2/M cell cycle arrest and ultimately reversed in vitro and in vivo chemoresistance of docetaxel-resistant LAD cells, at least partially in a miR-200b-dependent manner. HDAC1/4 suppression-induced rescue of miR-200b contributed to downregulation of E2F3, survivin and Aurora-A, and upregulation of cleaved-caspase-3. HDAC1/4 levels in docetaxel-insensitive human LAD tissues, inversely correlated with miR-200b, were upregulated compared with docetaxel-sensitive tissues. Taken together, our findings suggest that the HDAC1/4/Sp1/miR-200b/E2F3 pathway is responsible for chemoresistance of docetaxel-resistant LAD cells.

MicroRNAs: key players of taxane resistance and their therapeutic potential in human cancers.

The successful long-term use of taxane for cancer therapy is often prevented by the development of drug resistance in clinic. Thus, exploring the mechanisms involved is a first step towards rational strategies to overcome taxane resistance. Taxane resistance-related microRNA (miRNAs) are under investigation and miRNAs could induce the taxane resistance of tumour cells by regulating cell cycle distribution, survival and/or apoptosis pathways, drug transports, epithelial-mesenchymal transition and cancer stem cell. This article summarizes current research involving miRNAs as regulators of key target genes for tanxanxe chemoresistance and discusses the complex regulatory networks of miRNAs. Also, the authors will envisage future developments towards the potential use of targeting miRNAs as a novel strategy for improving response of tumour patients to taxane. miRNAs play critical roles in taxane chemoresistance and the miRNA-based therapies will be helpful for overcoming drug resistance and developing more effective personalized anti-cancer treatment strategies. Further research studies should be performed to promote therapeutic-clinical use of taxane resistance-related miRNAs in cancer patients, especially in those patients with taxane-resistant cancers.

MicroRNA-650 was a prognostic factor in human lung adenocarcinoma and confers the docetaxel chemoresistance of lung adenocarcinoma cells via regulating Bcl-2/Bax expression.

Increasing evidence shows that dysregulation of microRNAs (miRNAs) is involved in malignant transformation. We investigated the clinical significance of miR-650 and its involvement in chemoresistance to docetaxel. Our results showed that the relative expression level of miR-650 was significantly higher in LAD tissues than in corresponding nontumor tissues and high level of miR-650 expression was found to be significantly associated with high incidence of lymph node metastasis, advanced clinical stage and poor prognosis of LAD patients. Univariate and multivariate analyses indicated that high miR-650 expression was an independent prognostic factor for survival. Also, we found that the level of miR-650 in LAD tissues was correlated with the response of patients to docetaxel-based chemotherapy. Silencing of miR-650 could increase the in vitro sensitivity of docetaxel-resistant LAD cells to docetaxel, while upregulation of miR-650 decreased the sensitivity of parental LAD cells to docetaxel both in vitro and in vivo. Additionally, silencing of miR-650 could enhance the caspase-3-dependent apoptosis, which might be correlated with the decreased ratio of Bcl-2/Bax. Further researches suggested that inhibitor of growth 4 (ING4) was a direct target of miR-650. Downregulated or upregulated ING4 expression could partially rescue the effects of miR-650 inhibitor or mimics in docetaxel-resistant or parental LAD cells. Furthermore, we found that ING4 was upregulated in docetaxel-responding LAD tissues, and its expression was inversely correlated with miR-650. Thus, miR-650 is a novel prognostic marker in LAD and its expression is a potential indicator of chemosensitivity to docetaxel-based chemotherapy regimen.

The role of Aurora A in hypoxia-inducible factor 1α-promoting malignant phenotypes of hepatocelluar carcinoma.

Overexpression of both hypoxia-inducible factor 1α (HIF-1α) and Aurora A has been found in hepatocellular carcinoma (HCC). However, whether HIF-1α and Aurora A synergistically promote malignant phenotypes of HCC cells is unknown. The purpose of this study was to investigate the roles and functional correlation of HIF-1α and Aurora A in HCC progression. Immunohistochemistry was performed to detect HIF-1α and Aurora A protein expression in 55 primary HCC and corresponding non-tumor tissues and their clinical significance. Gene knockout technology using short hairpin RNA (shRNA) was used to knockdown expression of HIF-1α or Aurora A and analyze their effects on malignant phenotypes of HCC cells. The transcriptional regulation of Aurora A by HIF-1α and the possible downstream molecular signaling pathways were also determined. Results showed that hypoxia could induce the increased expression of HIF-1α and Aurora A in HCC cells. Also, shRNA-mediated HIF-1α downregulation could lead to the decreased Aurora A expression and inhibition of growth or invasion in HCC cells. Moreover, HIF-1α could transcriptionally regulate Aurora A expression by binding to hypoxia-responsive elements in the Aurora A promoter and recruiting the coactivator-p300/CBP. Additionally, shRNA-mediated Aurora A knockdown could mimic the effects of HIF-1α downregulation on phenotypes of HCC cells, and overexpression of Aurora A could partially rescue the phenotypical changes of HCC cells induced by HIF-1α downregulation. Further research indicated that activation of Akt and p38-MAPK signaling pathways mediated the downstream effects of HIF-1α and Aurora A in HCC cells under hypoxic condition. Taken together, our findings indicated that Aurora A might be a key regulator of HIF-1α-promoting malignant phenotypes of HCC by activation of Akt and p38-MAPK signaling pathways.

Let-7c governs the acquisition of chemo- or radioresistance and epithelial-to-mesenchymal transition phenotypes in docetaxel-resistant lung adenocarcinoma.

MicroRNA (miRNA) expression and functions have been reported to contribute to phenotypic features of tumor cells. Although targets and functional roles for many miRNAs have been described in lung adenocarcinoma (LAD), their pathophysiologic roles in phenotypes of chemoresistant LAD cells are still largely unclear. Previously, docetaxel (DTX)-resistant LAD cell lines (SPC-A1/DTX and H1299/DTX) were established by our laboratory and displayed chemo- or radioresistance and mesenchymal features with enhanced invasiveness and motility. Unbiased miRNA profiling indicated that let-7c (MIRLET7C) was significantly downregulated in SPC-A1/DTX cells. Ectopic let-7c expression increased the in vitro and in vivo chemo- or radiosensitivity of DTX-resistant LAD cells through enhanced apoptosis, reversal of epithelial-to-mesenchymal phenotypes, and inhibition of in vivo metastatic potential via inactivation of Akt phosphorylation, whereas a let-7c inhibitor decreased the chemo- or radiosensitivity of parental cells. Further investigation suggested that let-7c significantly reduced the luciferase activity of a Bcl-xL 3'-UTR-based reporter, concordant with reduced Bcl-xL protein levels. Additionally, siRNA-mediated Bcl-xL knockdown mimicked the same effects of let-7c precursor, and enforced Bcl-xL expression partially rescued the effects of let-7c precursor in DTX-resistant LAD cells. Furthermore, we found that Bcl-xL was significantly upregulated in DTX-nonresponding LAD tissues, and its expression was inversely correlated with let-7c expression. This study suggests an important role for let-7c in the molecular etiology of chemoresistant lung adenocarcinoma.