Overcoming 5-Fu resistance in human non-small cell lung cancer cells by the combination of 5-Fu and cisplatin through the inhibition of glucose metabolism.

5-Fu is a pyrimidine analog which is wildly used in the treatment of cancers. The development of strategies that increase its anticancer activity has been studied over the past 20 years. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU. In this study, we investigate the glucose metabolic profiles of non-small cell lung cancer cells in response to 5-Fu and cisplatin. Interestingly, the glucose metabolism of A549 cells is activated by 5-Fu treatment but suppressed by cisplatin treatment. We generalize 5-Fu-resistant and cisplatin-resistant cell lines from A549 cells. The glucose metabolism in 5-Fu-resistant cells is increased but decreased in cisplatin-resistant cells. In addition, glycolysis inhibition sensitizes lung cancer cells to 5-Fu. Importantly, we report a synergistic inhibitory effect on lung cancer cells by the combination of 5-Fu with cisplatin through the suppression of glucose metabolism both in vitro and in vivo. Moreover, restoration of glucose metabolism by overexpression of glycolytic key enzymes renders A549 cells resistant to 5-Fu. In summary, our study indicates that glycolysis inhibition contributes to the synergistic antitumor effect of combinational therapy, and targeting glycolysis could be an effective strategy for overcoming 5-Fu resistance in cancer therapy.

Development of a prognostic prediction model based on microRNA-1269a in esophageal cancer.

BACKGROUND: Esophageal cancer (ESCA) is a heterogeneous cancer with variable outcomes that are challenging to predict. MicroRNA (miR)-1269a is a newly discovered non-coding RNA that shows promising prognostic prediction in other cancers, but its clinical value in ESCA remains unclear. AIM: To explore the relationship between miR-1269a and its clinical value and to develop a nomogram to succinctly display this relationship. METHODS: We analyzed the expression of miR-1269a in 125 ESCA tissue samples with complete clinical data and 52 normal tissue samples. We determined the prognostic value of miR-1269a for overall survival (OS) and cancer-specific survival (CSS) and evaluated the association between miR-1269a and clinical variables including tumor location, histologic grade, metastatic stage, and American Joint Committee on Cancer (AJCC) stage using multivariate Cox analysis. Additionally, we developed a nomogram for OS and CSS based on miR-1269a expression using age and AJCC stage and assessed its prognostic performance. Using Gene Ontology and Kyoto Encyclopedia of Gene and Genomes analyses, we predicted the target genes of miR-1269a and analyzed their potential function in caner development. RESULTS: The expression of miR-1269a was significantly higher in ESCA patients than healthy controls. Patients with high expression of miR-1269a showed poor prognosis in OS and CSS, suffered increased rates of low differentiation and metastasis, and exhibited tumor stage T3 + T4, positive lymph stage, and AJCC stage III + IV. The area under the receiver operating characteristic curve of miR-1269a was 0.716 for OS and 0.764 for CSS. Multivariate Cox analysis revealed that AJCC stage and miR-1269a were independent factors for OS and CSS. Combing with age, we constructed a nomogram for prognostic prediction. Additionally, our nomogram showed excellent predictive performance for OS and CSS after 3 years and 5 years and was easy to use. Ultimately, the functional analysis suggested that miR-1269a was mostly involved in the PI3K-AKT signaling pathway. CONCLUSION: miR-1269a can be used as a potential indicator for the prognosis of ESCA patients. We developed an easy-to-use nomogram with excellent ESCA prognostic prediction for clinical use.

Expression and role of P-element-induced wimpy testis-interacting RNA in diabetic-retinopathy in mice.

BACKGROUND: As one of the major microvascular complications of diabetes, diabetic retinopathy (DR) is the leading cause of blindness in the working age population. Because the extremely complex pathogenesis of DR has not been fully clarified, the occurrence and development of DR is closely related to tissue ischemia and hypoxia and neovascularization The formation of retinal neovascularization (RNV) has great harm to the visual acuity of patients. AIM: To investigate the expression of P-element-induced wimpy testis-interacting RNA (piRNA) in proliferative DR mice and select piRNA related to RNV. METHODS: One hundred healthy C57BL/6J mice were randomly divided into a normal group as control group (CG) and proliferative DR (PDR) group as experimental group (EG), with 50 mice in each group. Samples were collected from both groups at the same time, and the lesions of mice were evaluated by hematoxylin and eosin staining and retinal blood vessel staining. The retinal tissues were collected for second-generation high-throughput sequencing, and the differentially expressed piRNA between the CG and EG was detected, and polymerase chain reaction (PCR) was conducted for verification. The differentially obtained piRNA target genes and expression profiles were enrichment analysis based on gene annotation (Gene Ontology) and Kyoto Encyclopedia of Genes and Genomes. RESULTS: In the CG there was no perfusion area, neovascularization and endothelial nucleus broke through the inner boundary membrane of retinap. In the EG, there were a lot of nonperfused areas, new blood vessels and endothelial nuclei breaking through the inner boundary membrane of the retina. There was a statistically significant difference in the number of vascular endothelial nuclei breaking through the inner retinal membrane between the two groups. High-throughput sequencing analysis showed that compared with the CG, a total of 79 piRNAs were differentially expressed in EG, among which 43 piRNAs were up-regulated and 36 piRNAs were down-regulated. Bioinformatics analysis showed that the differentially expressed piRNAs were mainly concentrated in the signaling pathways of angiogenesis and cell proliferation. Ten piRNAs were selected for PCR, and the results showed that the expression of piR-MMU-40373735, piR-MMU-61121420, piR-MMU-55687822, piR-MMU-1373887 were high, and the expression of piR-MMU-7401535, piR-MMU-4773779, piR-MMU-1304999, and piR-MMU-5160126 were low, which were consistent with the sequencing results. CONCLUSION: In the EG, the abnormal expression of piRNA is involved in the pathway of angiogenesis and cell proliferation, suggesting that piRNAs have some regulatory function in proliferative diabetic-retinopathy.

Risk factors of atrial fibrillation occurring after radical surgery of esophageal carcinoma.

BACKGROUND: Atrial fibrillation (AF) is a common complication after radical surgery of esophageal cancer. The aim of this study was to explore AF risk factors after radical surgery of esophageal carcinoma. METHOD: The data of 335 patients with esophageal cancer who were admitted in our hospital from January 2014 to August 2016 for the first time were retrospectively analyzed. We retrieved the papers in some data banks using the search terms including English and Chinese search terms, and obtained 13 factors which were mentioned in more than 6 papers. The 13 factors including age, gender, history of smoking, history of hypertension, history of peripheral vascular disease, history of cardiac stents or angina pectoris, preoperative pulmonary infection, preoperative brain natriuretic peptide (BNP) level, preoperative left ventricular diastolic dysfunction, operative method, lesion location, intraoperative blood transfusion, adhesion between lymph nodes and pericardium, underwent univariate and multivariate analyses. RESULTS: Of the 335 patients with esophageal cancer, 48 had AF within one week after operation. Univariate analysis indicated that the age (OR: 4.89; CI: 2.53-9.47, P: 0.000), gender (OR: 2.26; CI: 1.17-4.37, P: 0.013), history of peripheral vascular disease (OR: 2.29; CI: 1.06-4.92, P: 0.030), history of cardiac stents or angina pectoris (OR: 27.30; CI: 12.44-59.91, P: 0.000), preoperative BNP level (OR: 27.13; CI: 10.97-67.06, P: 0.000), preoperative left ventricular diastolic dysfunction (OR: 2.22; CI: 1.19-4.14, P: 0.012), operative method (OR: 2.09; CI: 1.002-4.380, P: 0.046), intraoperative blood transfusion (OR: 20.24; CI: 8.39-48.82, P: 0.000), and adhesion between lymph nodes and pericardium were risk factors (OR: 2.05; CI: 1.08-3.87, P: 0.024). Furthermore, multivariate analysis displayed that advanced age (OR: 5.044; CI: 1.748-14.554, P: 0.003), male (OR: 6.161; CI: 2.143-17.715, P: 0.001), history of cardiac stents or angina pectoris (OR: 48.813; CI: 13.674-174.246, P: 0.000), preoperative BNP > 100 (OR: 41.515; CI: 9.380-183.732, P: 0.000), open surgery (OR: 3.357; CI: 1.026-10.983, P: 0.045), intraoperative blood transfusion (OR: 58.404; CI: 10.777-316.509, P: 0.000), and adhesion between lymph nodes and pericardium (OR: 3.954; CI: 1.364-11.459, P: 0.011) were risk factors which could increase the incidence of postoperative AF. CONCLUSION: We should pay attention to the above risk factors in order to reduce the incidence of postoperative AF.

Construction of a competing endogenous RNA network using differentially expressed lncRNAs, miRNAs and mRNAs in non­small cell lung cancer.

The competing endogenous RNA (ceRNA) network is crucial for the development and progression of tumors, including non­small cell lung cancer (NSCLC). However, what type of ceRNA network regulates NSCLC has not been clarified. The present study aimed to elucidate the long non­coding RNA (lncRNA)/microRNA (miRNA)/mRNA ceRNA network in NSCLC, particularly for the significance of lncRNAs in NSCLC. NSCLC­specific differentially expressed lncRNAs, miRNAs and mRNAs in the Cancer Genome Atlas (TCGA) were analyzed and their relationship was analyzed by a ceRNA network. Their potential functions of differentially expressed mRNAs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Furthermore, the expression levels of four selected lncRNAs in TCGA were determined and their associated survival of patients was examined. In addition, the expression profiles of these four lncRNAs in 48 NSCLC specimens and cell lines, their cellular distribution and associated clinical parameters were examined. We successfully constructed a ceRNA network, including 113 lncRNAs, 12 miRNAs and 36 mRNAs differentially expressed between NSCLC and non­tumor tissues. LINC00525, MED4­AS1, STEAP2­AS1 and SYNPR­AS1 lncRNAs were selected and validated for their association with the survival of NSCLC patients. The expression of these lncRNAs was upregulated in 48 NSCLC tissues and was varying in NSCLC cells. While LINC00525 was mainly expressed in the cytoplasm, MED4­AS1 was in both the nucleus and cytoplasm of A549 cells. In addition, the expression of LINC00525 was significantly associated with smoking history (P<0.05); MED4­AS1 was significantly associated with women, poor differentiation and lymph node metastasis (P<0.05); STEAP2­AS1 was significantly associated with women (P<0.01); and SYNPR­AS1 was significantly associated with women and adenocarcinoma (P<0.05). These lncRNAs may be valuable biomarkers for prognosis of NSCLC and the ceRNA network may provide new insights in the pathogenesis of NSCLC.

Clinical effect and action mechanism of Weicao Capsule in treating gout.

OBJECTIVE: To study the therapeutic effect of Weicao Capsule (WCC) on gout. METHODS: Two hundred gout patients were assigned to two groups. The treated group was treated with WCC and the control group was treated with Tongfengding Capsule. Both groups were given the respective treatments orally 3 times a day, 2 capsules each time with 2 weeks as one course and all patients received 2 successive courses of treatment. Changes of blood beta(2)-microglobulin (beta(2)-M), hemoglobin (Hb), 24 h urinary protein (24 h UP), pH value of urine and blood uric acid (BUA) as well as kidney function were observed. RESULTS: After treatment, level of beta(2)-M got lowered significantly, Hb and 24 h UP, blood urea nitrogen, serum creatinine and the clearance rate of creatinine, as well as blood lipids all improved obviously in the treated group (all P<0.01), while these parameters remained unchanged in the control group (P>0.05). The pH value of urine was improved in both groups showing an insignificant difference between them (P>0.05). BUA was decreased in both groups with a decrease to a larger extent in the treated group (P<0.01). The total effective rate was 87% in the treated group, which was superior to that in the control group (62%, P<0.05). CONCLUSION: WCC has a favorable therapeutic effect on gout and its mechanism of action for improving renal function and reducing urinary protein could be related with the lowering of blood beta(2)-M, BUA and lipids.

Zinc finger protein ZBTB20 promotes cell proliferation in non-small cell lung cancer through repression of FoxO1.

In the present study, we found that ZBTB20, a member of the POK (POZ and Krüppel) family of transcriptional repressors, was significantly up-regulated in lung cancer tissues, compared with adjacent normal tissues. Our in vitro studies further found that ZBTB20 overexpression promoted, while its inhibition using small interfering RNA suppressed cell proliferation. Consistently, key regulators in cell-cycle progression, such as Cyclin D1, Cyclin E, P21 and P27, were also regulated by ZBTB20. At the molecular level, we further revealed that FoxO1, a tumor suppressor in multiple human cancers, was transcriptionally repressed by ZBTB20. Therefore, our results highlight an important role for ZBTB20 in controlling NSCLC development, which might be helpful to identify potential therapeutic targets for its treatment.

Identification of potential biomarkers for clear cell renal cell carcinoma based on microRNA-mRNA pathway relationships.

BACKGROUND: MicroRNAs (miRNAs) play important roles in tumor genesis. miRNA dysregulation has been widely studied and demonstrated in clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: We applied a newly proposed method for selecting miRNAs that discriminate between healthy controls and cancers. We initially extracted different miRNAs and mRNAs and then selected miRNA-mRNA dysregulation pairs. The pathways that involved mRNAs were acquired according to the functional enrichment. We integrated the miRNAs, mRNAs, and pathways and constructed the miRNA-mRNA pathway relationships based on the derived significant miRNAs. RESULTS: We acquired 566 antiregulated miRNA-mRNA pairs including 56 miRNAs and 485 mRNAs. Three significant pathways related to ccRCC, namely, arginine and proline metabolism, aldosterone-regulated sodium reabsorption, and oxidative phosphorylation, were observed. Based on the miRNA-mRNA pathway relationships, five significant miRNAs were identified as potential biomarkers: hsa-miR-425, hsa-miR-136, hsa-miR-335, hsa-miR-340, and hsa-miR-320d. CONCLUSION: This integrative network approach revealed important miRNAs in the ccRCC that can identify specific disease biomarkers, which can be used as targets for cancer treatment.