Novel miR-490-3p/hnRNPA1-b/PKM2 axis mediates the Warburg effect and proliferation of colon cancer cells via the PI3K/AKT pathway.

BACKGROUND: Heterogeneous ribonucleoprotein A1 (hnRNPA1) has been reported to enhance the Warburg effect and promote colon cancer (CC) cell proliferation, but the role and mechanism of the miR-490-3p/hnRNPA1-b/PKM2 axis in CC have not yet been elucidated. AIM: To investigate the role and mechanism of a novel miR-490-3p/hnRNPA1-b/PKM2 axis in enhancing the Warburg effect and promoting CC cell proliferation through the PI3K/AKT pathway. METHODS: Paraffin-embedded pathological sections from 220 CC patients were collected and subjected to immunohistochemical analysis to determine the expression of hnRNPA1-b. The relationship between the expression values and the clinicopathological features of the patients was investigated. Differences in mRNA expression were analyzed using quantitative real-time polymerase chain reaction, while differences in protein expression were analyzed using western blot. Cell proliferation was evaluated using the cell counting kit-8 and 5-ethynyl-2'-deoxyuridine assays, and cell cycle and apoptosis were detected using flow cytometric assays. The targeted binding of miR-490-3p to hnRNPA1-b was validated using a dual luciferase reporter assay. The Warburg effect was evaluated by glucose uptake and lactic acid production assays. RESULTS: The expression of hnRNPA1-b was significantly increased in CC tissues and cells compared to normal controls (P < 0.05). Immunohistochemical results demonstrated significant variations in the expression of the hnRNPA1-b antigen in different stages of CC, including stage I, II-III, and IV. Furthermore, the clinicopathologic characterization revealed a significant correlation between hnRNPA1-b expression and clinical stage as well as T classification. HnRNPA1-b was found to enhance the Warburg effect through the PI3K/AKT pathway, thereby promoting proliferation of HCT116 and SW620 cells. However, the proliferation of HCT116 and SW620 cells was inhibited when miR-490-3p targeted and bound to hnRNPA1-b, effectively blocking the Warburg effect. CONCLUSION: These findings suggest that the novel miR-490-3p/hnRNPA1-b/PKM2 axis could provide a new strategy for the diagnosis and treatment of CC.

High Level of Adropin Promotes the Progression of Pancreatic Ductal Adenocarcinoma.

BACKGROUND AND OBJECTIVE: Preliminary experiments have revealed the abnormally high expression level of adropin in pancreatic ductal adenocarcinoma (PDA). This study investigated the role of adropin in the progression of PDA. METHODS: The paraffin-embedded samples of 20 patients with PDA were obtained from the hospital biobank, and immunohistochemistry was used to evaluate adropin expression. PDA cell lines were cultured and treated with recombinant adropin or adropin knockdown. Cell behavior was assessed, and the expression of phospho-vascular endothelial growth factor receptor (p-VEGFR2) and other related proteins was detected. The cell-derived xenograft (CDX) of PDA was established, and the effects of adropin or adropin knockdown on tumor growth were observed. RESULTS: The PDA cancer tissues exhibited elevated adropin protein expression compared with the paracancerous tissues, and the expression was positively correlated with carbohydrate antigen 19-9 levels in patients. Adropin significantly promoted the proliferation and migration of PDA cells and upregulated the expression of p-VEGFR2, Ki67, cyclin D1, and matrix metalloprotein 2 (MMP2). After the knockdown of adropin expression or blockade of VEGFR2, the above effects of adropin were significantly reversed. Adropin supplementation significantly accelerated tumor growth in PDA CDX; upregulated the expression of p-VEGFR2, Ki67, cyclin D1, and MMP2; and promoted angiogenesis in tumor tissue microenvironment. However, CDX inoculated with adropin knockdown cells produced the opposite results. CONCLUSION: Adropin overexpression in PDA promotes cancer cell proliferation and angiogenesis in tumor microenvironment by continuously activating VEGFR2 signaling, thereby creating conditions for tumor progression. Thus, targeting adropin may be an effective anti-PDA strategy.

Ascending colon cancer and situs inversus totalis - altered surgeon position for successful laparoscopic hemicolectomy: A case report.

BACKGROUND: Situs inversus totalis (SIT) is a rare congenital condition in which the structure of the abdominal and thoracic cavities is the mirror image of normal. This anatomic reversal makes laparoscopic surgery difficult when treating colorectal cancer. CASE SUMMARY: We describe the successful laparoscopic hemicolectomy of a 68-year-old Chinese woman with SIT and ascending colon cancer. Based on preoperative imaging and careful consideration of the patient's anatomy, the position of the surgeon was modified such that the surgeon stood between her legs, while the surgical assistant and endoscopist stood to the surgeon's left. Trocar position was also adjusted appropriately. The surgery lasted 178 min, during which the patient lost 50 mL of blood. Pathology analysis of the resected tumor confirmed an adenocarcinoma in clinical stage pT3N0M0, without lymph node involvement. The patient experienced no postoperative complications and was discharged 10 d after surgery. CONCLUSION: This case illustrates that careful positioning of the surgeon can facilitate laparoscopic surgery of SIT patients.

Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer.

Enhancer of zeste homolog 2 (EZH2) is abnormally highly expressed in pancreatic cancer (PC). However, it is not ideal to treat PC by inhibiting EZH2. This study reported that the combined use of pan-peroxisome proliferator-activated receptor (PPAR) agonist could significantly improve the anti-PC effect of EZH2 inhibitor. In vitro, PC cell lines PANC-1 and AsPC-1 were cultured, and MTT and flow cytometry were performed to observe the effects of pan-PPAR agonist bezafibrate and EZH2 selective inhibitor GSK126 on cell viability and apoptosis. In vivo, CDXs of PANC-1 and AsPC-1 were established to observe the effects of bezafibrate and GSK126 on bearing tumors. Western blotting was performed to detect the protein expressions of H3K27me3, ß-catenin, p-ß-catenin, cyclin D1, c-Myc, and cleaved caspase 3 in vitro and in vivo. The results showed that bezafibrate significantly improved the effects of GSK126 on proliferation inhibition and apoptosis promotion in vitro and the growth suppression of CDX tumors in vivo. It also significantly enhanced the effects of GSK126 on upregulating the expression level of p-ß-catenin and that of cleaved caspase 3 in vitro and in vivo. In parallel, downregulation of the expression levels of H3K27me3, ß-catenin, cyclin D1, and c-Myc was also observed in vitro or in vivo. These results suggest that the combination of bezafibrate and GSK126 has synergistic effects on PC, and the molecular mechanism may be related to the enhanced inhibition of the Wnt/ß-catenin signaling pathway. We believe that targeting the EZH2-PPAR axis is a potential therapeutic pathway for PC.

Assessment of circulating tumor DNA in cerebrospinal fluid by whole exome sequencing to detect genomic alterations of glioblastoma.

BACKGROUND: Cerebrospinal fluid (CSF) has been demonstrated as a better source of circulating tumor DNA (ctDNA) than plasma for brain tumors. However, it is unclear whether whole exome sequencing (WES) is qualified for detection of ctDNA in CSF. The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma. METHODS: CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery, Sun Yat-sen University Cancer Center. ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES. The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared. RESULTS: Due to the ctDNA in CSF was unqualified for exome sequencing for one patient, nine patients were included into the final analysis. More glioblastoma-associated mutations tended to be detected in CSF compared with the corresponding tumor tissue samples (3.56 ±â€Š0.75 vs. 2.22 ±â€Š0.32, P = 0.097), while the statistical significance was limited by the small sample size. The average mutation frequencies were similar in CSF and tumor tissue samples (74.1% ±â€Š6.0% vs. 73.8% ±â€Š6.0%, P = 0.924). The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3 histone, family 3A (H3F3A) which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES. Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF. CONCLUSION: Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma, which may provide useful information for the decision of treatment strategy.

Link between risk of colorectal cancer and serum vitamin E levels: A meta-analysis of case-control studies.

BACKGROUND: The effect of low serum vitamin E levels on the risk of colorectal cancer (CRC) remains inconclusive. This meta-analysis aims to synthesize relevant studies to evaluate the association between serum vitamin E and the risk of CRC based on case-control studies. METHODS: Potentially relevant studies were selected by searching PubMed, EMBASE, and China National Knowledge Infrastructure databases according to inclusion and exclusion criteria. The association between serum vitamin E levels and CRC was estimated by the weighted mean difference (WMD) and 95% confidence interval (CI) using a random-effects model. Heterogeneity was evaluated using Q test and I statistic. Subgroup analysis was conducted to explore sources of heterogeneity. Sensitivity analysis was performed to reveal stability and reliability. RESULTS: A total of 10 papers with 11 studies, including 6431 subjects with 520 CRC patients and 5981 controls, were included in this present meta-analysis. The results indicated that compared with healthy controls, patients with CRC showed lower concentrations of serum vitamin E (WMD = -2.994 µmol/L, 95% CI = -4.395 to -1.593). Ethnicity subgroup analysis indicated that the serum vitamin E levels were lower in European (WMD = -1.82 µmol/L, 95% CI = -3.00 to -0.65), but not in Asian. Control-source subgroup analysis revealed that a significant association was observed in subgroup with hospital-based controls (WMD = -3.43 µmol/L, 95% CI = -6.27 to -0.59), but not in those with population-based controls. Sensitivity analysis suggested no significant difference in the pooled estimates, indicating stable results. CONCLUSIONS: CRC is associated with a lower concentration of serum vitamin E. However, necessary prospective cohort studies should be conducted to assess the effect of serum vitamin E on the risk of CRC in the future.

miR-216b promotes cell growth and enhances chemosensitivity of colorectal cancer by suppressing PDZ-binding kinase.

PDZ-binding kinase (PBK/TOPK) acts as oncogene in various cancers and correlates with drug response. However, few studies have examined the expression and roles of PBK in colonrectal cancer (CRC). In this study, we found a significant increase in the expression of PBK in CRC tissues and cell lines. While overexpression of PBK promoted cell growth and decreased the toxicity effect of oxaliplation (OXA), targeting PBK with short hairpin RNA (shRNA) or novel PBK inhibitor HI-TOPK-032 effectively suppressed tumor growth and potentiated chemosensitivity in vitro and in vivo. Furthermore, there was a significant inverse correlation between the expressions of miR-216b and PBK. Further found that miR-216b could down-regulate PBK levels by binding to the 3' untranslated region (3'UTR) of PBK. Notably, while miR-216b decreased cell proliferation and enhanced sensitivity of CRC cells to oxaliplation, re-expression of PBK dramatically reversed these events. Collectively, our data indicated that miR-216b may function as a tumor suppressor though regulating PBK expression, which provided promising targets and possible therapeutic strategies for CRC treatment.

Increased PTOV1 expression is related to poor prognosis in epithelial ovarian cancer.

Altered expression of prostate tumor overexpressed-1 (PTOV1) is observed in various types of human cancers. However, the role of PTOV1 in epithelial ovarian cancer (EOC) remains unclear. PTOV1 messenger (m)RNA expression in EOC patients was evaluated by quantitative real-time PCR (qRT-PCR). PTOV1 protein expression was also analyzed in archived paraffin-embedded EOC tissues using immunohistochemistry (IHC), and its association with overall survival of patients was analyzed by statistical analysis. Results from qRT-PCR analysis show that the expression level of PTOV1 mRNA was significantly higher in tumor tissues of EOC, compared to that in adjacent noncancerous tissues (P < 0.001). IHC staining showed that high expression of PTOV1 was detected in 57.2 % (87/152) of EOC cases. High expression of PTOV1 was significantly associated with pathological grade (P = 0.029) and clinical stage (P = 0.001). Moreover, the results of Kaplan-Meier analysis indicated that a high expression level of PTOV1 resulted in a significantly poor prognosis of EOC patients. Multivariate analysis showed that high expression of PTOV1 was an independent prognostic factor for overall survival (P < 0.001). In conclusion, PTOV1 protein abnormal expression might contribute to the malignant progression of EOC. High expression of PTOV1 predicts poor prognosis in patients with EOC.