microRNA-497 slows esophageal cancer development and reverses chemotherapy resistance through its target QKI.

Esophageal cancer (EC) is considered one of the most lethal cancers in human beings, and multiple miRNAs have been investigated to be involved in EC development by targeting their target genes. However, the function and related mechanism of miRNA-497 on EC tumorigenesis remain uncertain. This study first demonstrated that the expression levels of miR-497 in esophageal cancer specimens and cells were down-regulated. Forced expression of miR-497 inhibited cell proliferation, tube formation and migration in EC cells. To further investigate the potential molecular mechanism of miR-497 suppression in regulating EC, we found that miR-497 directly binds to the 3'-untranslational region of QKI, miR-497 overexpression suppressed QKI expression. We further found that overexpression of miR-497 enhanced the effect of chemotherapy in EC cell lines, and prevented the tumor growth of EC in vivo. Our findings indicated that miR-497 suppression increased QKI expression and therapeutic resistance of esophageal cancer, which is likely to be a biomarker of EC progression and potential therapeutic target.

Knockdown of long non-coding RNA AGAP2-AS1 suppresses the proliferation and metastasis of glioma by targeting microRNA-497-5p.

Long non-coding RNA (LncRNA) AGAP2-AS1 has been demonstrated to involve in various malignancies. However, the expression and biological effect of AGAP2-AS1 on glioma remain enigmatic. We aimed to explore the effects of AGAP2-AS1 on glioma. Expressions and relationship of AGAP2-AS1 and microRNA-497-5p (miR-497-5p) in different grades of glioma tissues and cell lines as well as normal ones were assessed by quantitative real-time polymerase chain reaction (qRT-PCR), starBase, and dual-luciferase reporter assay. In addition, the effect of AGAP2-AS1 on the cell biological behaviors, epithelial-mesenchymal transition (EMT)-related markers, and miR-497-5p level was detected by cell functional experiments, western blot, and qRT-PCR. After transfection with miR-497-5p mimic (M), inhibitor (I), and AGAP2-AS1 knockdown, miR-497-5p level, cell biological behaviors, and EMT-related markers were detected again. AGAP2-AS1 expression was increased while miR-497-5p expression was decreased in glioma tissues and cell lines, and increase of AGAP2-AS1 expression or reduction of miR-497-5p expression was also correlated with clinicopathological grades of glioma. Furthermore, AGAP2-AS1 knockdown repressed cell biological behaviors and EMT-related markers expressions. Mechanically, AGAP2-AS1 targeted miR-497-5p and AGAP2-AS1 knockdown led to elevation of miR-497-5p expression. In addition, rescue experiments were conducted to validate the vital influence of miR-497-5p on the AGAP2-AS1-regulated proliferation and metastasis of glioma. AGAP2-AS1 may serve as an oncogene in the tumorigenesis of glioma by inhibiting miR-497-5p expression, showing its potential as a prognostic biomarker and a therapeutic target for glioma.

The Expression of Circulating miR-497 and Metadherin in Hepatocellular Carcinoma: Relation to the Tumor Characteristics and Patients' Survival.

Objectives: This study aimed to evaluate the prognostic significance and relationship of miR-497 and metadherin to hepatocellular carcinoma (HCC) tumor characteristics and patients' survival. Methods: This study enrolled 120 (60 HCC patients and 60 healthy) subjects. Serum miR-497 and metadherin mRNA relative expression were analyzed by real-time quantitative reverse transcription polymerase chain reaction. The overall survival (OS) of HCC patients was assessed using the Kaplan-Meier curve and log-rank test. Results: Serum miR-497 showed statistically significant downregulation in HCC patients compared to controls (p < 0.001). Serum metadherin mRNA relative expression was significantly upregulated in HCC patients compared to controls (p < 0.001). Both serum miR-497 and metadherin mRNA expression were significantly associated with the number of tumor foci (p = 0.028 and 0.001, respectively), tumor size (p = 0.022 and <0.001, respectively), nodal metastasis (p = 0.003 and 0.003, respectively), distant metastasis (p = 0.003 and 0.003, respectively), vascular invasion (p = 0.040 and <0.001, respectively), and BCLC staging (p = 0.043 and 0.004, respectively). The overall survival was lower in patients with low miR-497 expression (p = 0.046) and in patients with high metadherin expression (p < 0.001). Conclusions: The expression levels of miR-497 showed downregulation in HCC patients, but metadherin expression showed upregulation. Both markers were inversely related and closely correlated with tumor characteristics and patients' survival.

The Diagnostic Value of Plasma miRNA-497, cTnI, FABP3 and GPBB in Pediatric Sepsis Complicated with Myocardial Injury.

OBJECTIVE: To investigate the diagnostic value of plasma miRNA-497, cardiac troponin I (cTnI), fatty acid binding protein 3 (FABP3), glycogen phosphorylase isoenzyme BB (GPBB) in pediatric sepsis complicated with myocardial injury. METHODS: From August 2018 to February 2020, 82 children with sepsis admitted to our hospital and 50 health children who came for physical examination (defined as control group) were enrolled in this study. Children with sepsis and myocardial injury were enrolled in the combined group (n=35), and those without myocardial injury were enrolled in the sepsis group (n=47). General data of three groups were collected, and the levels of miRNA-497, FABP3, GPBB, creatine kinase isoenzyme MB (CK-MB), procalcitonin (PCT), C-reactive protein (CRP), cTnI and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were detected and the cardiac function was measured. The diagnostic value of plasma miRNA-497, cTnI, FABP3 and GPBB in pediatric sepsis complicated with myocardial injury was analyzed. RESULTS: The infection site of the combined group was not significantly different from that of the sepsis group. The levels of miRNA-497, FABP3, GPBB, CK-MB, PCT, CRP, cTnI, NT-proBNP in the combined group were all higher than those in the sepsis group and the control group (P<0.05), and the left ventricular ejection fraction (LVEF) in the combined group was significantly lower than that in the other two group (P<0.05). The area under the curve (AUC) of the combination of miRNA-497, FABP3, GPBB, and cTnI in the diagnosis of sepsis complicated with myocardial injury was significantly higher than that of CK-MB, PCT, CRP, NT-proBNP alone (P<0.05), but there was no significant difference when compared with miRNA-497, FABP3, GPBB and cTnI alone (P>0.05). When the optimal thresholds of miRNA-497, FABP3, GPBB, and cTnI were set to 2.03, 6.23ng/mL, 4.01ng/mL, 1.23ng/mL, respectively, the sensitivity was 95.65%, 88.89%, 82.61%, 87.50%, respectively; the specificity was 83.33%, 94.12%, 83.33%, 90.91%, respectively; and the accuracy was 91.43%, 91.43%, 82.86%, 88.57%, respectively. Pearson correlation analysis indicating that miRNA-497 was positively correlated with the levels of FABP3, GPBB, and cTnI in the combined group (r=0.821, 0.621, 0.782, P<0.05). CONCLUSION: Plasma miRNA-497, cTnI, FABP3, and GPBB levels were increased in pediatric sepsis complicated with myocardial injury, and their combination had high diagnostic value, which was of great clinical significance for early diagnosis and early treatment of pediatric sepsis complicated with myocardial injury.

Accelerated wound healing in diabetic mice by miRNA-497 and its anti-inflammatory activity.

Diabetic foot ulcers represent one of the major and rising health issues, as the number of diabetic patients is increasing. MicroRNAs (miRNAs) are among various bioactive molecules under investigation for diabetic wound healing. The prolonged pro-inflammatory phase in diabetic wounds partly attributes to its non-healing nature. Therefore, we hypothesized that miRNA-497, known for its regulation of inflammatory responses, would enhance diabetic wound healing. We screened miRNA candidates, including miRNA-497 in the wounded skin of streptozotocin-induced type 1 diabetic mice. The therapeutic potential of miRNA-497 mimic was studied by intradermal injection around the wound in diabetic mice. In addition, the effects of miRNA-497 on pro-inflammatory cytokines were analyzed in the wound lesion of diabetic mice, and in human dermal fibroblasts cells exposed to high glucose and lipopolysaccharide.We found a significant reduction of miRNA-497 expression in the dermal wounds of the diabetic mice relative to normal mice. Intradermal injection of miRNA-497 around the full-thickness dermal wounds in diabetic mice accelerated wound closure effectively compared to the control miRNA. miRNA-497 treatment in vivo and in vitro decreased representative pro-inflammatory cytokines such as IL-1ß, IL-6, and TNF-α. Such anti-inflammatory effects of miRNA-497 shed light on its role in accelerating diabetic wound healing. In conclusion, miRNA-497, with its down-regulation activity for pro-inflammatory cytokines, is proposed as a potential therapeutic agent for diabetic wound healing.

MicroRNA-497 suppress osteosarcoma by targeting MAPK/Erk pathway.

BACKGROUND: The aim of this study was to study the mechanism of miRNA-497 in the apoptosis of osteosarcoma cells. METHODS: MG-63 cells were divided into the three groups: NC, BL and miRNA groups, NC group were treated with nothing; BL group were transfected with blank vector; miRNA group were transfected with miRNA-497. Cell proliferation rate was detected by MTT method; Apoptosis rate was detected by flow cytometry and measuring the gene and protein expression of MAPK, Erk and P 21 by RT-PCR and Western blot. RESULTS: The cell proliferation rate of miRNA group was significantly lower compared to NC group and BL group (p < 0.05); while the apoptosis rate of miRNA group (32.17 ± 3.23 %) was significantly higher than that of NC group  (8.40 ± 1.78 %) and BL group (8.83 ± 0.99 %) (p < 0.05, respectively). Regarding the gene expression detection, we found that gene and protein expressions of MAPK, Erk and P21 of miRNA group were significantly different compared to NC and BL groups (p < 0.05, respectively). CONCLUSION: MiR-497 can activate P21 expression by inhibiting the expression of MAPK/Erk signaling pathway, thus promoting the apoptosis of osteosarcoma cells (Fig. 5, Ref. 18).

Low-dose DNA-demethylating agent enhances the chemosensitivity of cancer cells by targeting cancer stem cells via the upregulation of microRNA-497.

PURPOSE: The DNA-demethylating agent decitabine has shown clinical response for the treatment of hematological malignancies and solid tumors, while the mechanisms underlying its antitumor capacity are not fully understood. METHODS: The sensitivities of cancer cells to different chemotherapeutic drugs, such as cisplatin, paclitaxel, and 5-FU, were detected. The tumor sphere formation assay was used to evaluate the effects of low-dose decitabine on cancer-initiating stem cells. RESULTS: We observed that the chemotherapy sensitivity of various cancer cells was enhanced following non-toxic low-dose decitabine treatment. Moreover, low-dose decitabine treatment suppressed the self-renewal of cancer-initiating cells and inhibited the expression of pluripotency markers. Strikingly, low-dose decitabine was able to augment chemosensitivity in cancer stem cells, likely by the upregulation of miRNA-497, which was reported to be downregulated and to have promoted cell apoptosis in multiple cancers. CONCLUSIONS: These results indicated that the DNA-demethylating agent could target cancer stem cells and reverse their chemotherapeutic resistance by regulating the endogenous expression of microRNAs.

miR-199a and miR-497 Are Associated with Better Overall Survival due to Increased Chemosensitivity in Diffuse Large B-Cell Lymphoma Patients.

Micro-RNAs (miRNAs) are short non-coding single-stranded RNA molecules regulating gene expression at the post-transcriptional level. miRNAs are involved in cell development, differentiation, apoptosis, and proliferation. miRNAs can either function as tumor suppressor genes or oncogenes in various important pathways. The expression of specific miRNAs has been identified to correlate with tumor prognosis. For miRNA expression analysis real-time PCR on 81 samples was performed, including 63 diffuse large B-cell lymphoma (DLBCL, 15 of germinal center B-cell like subtype, 17 non germinal center B-cell, 23 transformed, and eight unclassified) and 18 controls, including nine peripheral B-cells, 5 germinal-center B-cells, four lymphadenitis samples, and 4 lymphoma cell lines (RI-1, SUDHL4, Karpas, U2932). Expression levels of a panel of 11 miRNAs that have been previously involved in other types of cancer (miR-15b_2, miR-16_1*, miR-16_2, miR-16_2*, miR-27a, miR-27a*, miR-98-1, miR-103a, miR-185, miR-199a, and miR-497) were measured and correlated with clinical data. Furthermore, cell lines, lacking miR-199a and miR-497 expression, were electroporated with the two respective miRNAs and treated with standard immunochemotherapy routinely used in patients with DLBCL, followed by functional analyses including cell count and apoptosis assays. Seven miRNAs (miR-16_1*, miR-16_2*, miR-27a, miR-103, miR-185, miR-199, and miR-497) were statistically significantly up-regulated in DLBCL compared to normal germinal cells. However, high expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL.