COL11A1-driven positive feedback loop modulates fibroblast transformation and activates pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common leading causes of cancer death. The cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) aggravate the malignant behavior of PDAC. However, it is still unknown how PDAC induces normal fibroblasts (NFs) to CAFs. In present research, we found that PDAC-derived collagen type XI alpha 1 (COL11A1) promoted the conversion of NFs to CAF-like cells. It included morphological and corresponding molecular marker changes. Activation of the nuclear factor-κB (NF-κB) pathway was involved in this process. Corresponding, CAFs cells could secrete interleukin 6 (IL-6), which promoted the invasion and the epithelial-mesenchymal transition of PDAC cells. Furthermore, IL-6 promoted the expression of transcription factor Activating Transcription Factor 4 by activating the Mitogen-Activated Protein Kinase/extracellular-signal-regulated kinase pathway. The latter directly promotes the expression of COL11A1. This way, a feedback loop of mutual influence was constructed between PDAC and CAFs. Our research proposed a novel concept for PDAC-educated NFs. PDAC-COL11A1-fibroblast-IL-6-PDAC axis might contribute to the cascade between PDAC and TME.

LncRNA DHRS4-AS1 ameliorates hepatocellular carcinoma by suppressing proliferation and promoting apoptosis via miR-522-3p/SOCS5 axis.

Recent years have seen much effect in revealing the pathological association between lncRNA and HCC. Herein, we identified lncRNA DHRS4-AS1 as a potential tumor suppressor in HCC. Firstly, it was discovered that DHRS4-AS1 was significantly down-regulated in HCC tissues compared to normal tissues based on the database TCGA. It was also detected in a lower-than-usual expression quantity in HCC tissues we collected and HCC cell lines. Kaplan-Meier survival analysis revealed that high expression of DHRS4-AS1 contributed to higher overall survival rate of HCC patients.DHRS4-AS1 expression was significantly correlated to tumor size (P = 0.02) and TNM stage (P = 0.045). CCK-8, BrdU and colony-forming assays collectively demonstrated that overexpression of DHRS4-AS1 significantly restrained HCC cell proliferation. In vivo xenograft animal experiment showed that DHRS4-AS1 could efficiently preclude the tumor growth of HCC. Further investigation performed using flow cytometry and western blot showed that DHRS4-AS1 exerted its effects by accelerating cell apoptosis and capturing cell cycle in G0/G1 phase. Our study subsequently lucubrated that miR-522-3p was a negative target of DHRS4-AS1. Increased expression level of miR-522-3p was examined in HCC tissues and cell lines. Similarly, miR-522-3p mimics could reverse the inhibitory effect on HCC brought by DHRS4-AS1. SOCS5 was then discovered as a down-stream target of miR-522-3p, which suggested that SOCS5 participated in DHRS4-AS1/miR-522-3p axis to collectively mediate the development of HCC. Our study provides lncRNA DHRS4-AS1/miR-522-3p/SOCS5 axis as a novel target for HCC therapeutic strategy with potentiality.

Long non-coding RNA HCP5 functions as a sponge of miR-29b-3p and promotes cell growth and metastasis in hepatocellular carcinoma through upregulating DNMT3A.

Multiple studies have revealed that long non-coding RNA (lncRNAs) served as regulatory factors in modulating tumorigenesis of hepatocellular carcinoma (HCC). In the present study, we demonstrated that lncRNA HCP5 was overexpressed in HCC tissues and cell lines, and these findings were obvious even in metastatic and recurrent cases. Knockdown of HCP5 significantly alleviated cell growth, metastasis, and invasion both in vitro and in vivo through promoting apoptosis and by inactivating the epithelial-mesenchymal transition (EMT) progress. Moreover, miR-29b-3p has been identified as a negatively regulatory target gene of HCP5, and served as a tumor suppressor of HCC to prevent cell proliferation, migration, and invasion. Subsequently, DNMT3A was identified as a downstream regulatory factor of miR-29b-3p, and acted as a participated element of HCC progression by activating AKT phosphorylation. Taken together, our study elucidated for the first time that HCP5 plays a crucial role in HCC via the HCP5/miR-29b-3p/DNMT3A/AKT axis and our findings demonstrated a novel diagnostic and therapeutic strategy with potentiality to treat HCC.

LncRNA TTN-AS1 intensifies sorafenib resistance in hepatocellular carcinoma by sponging miR-16-5p and upregulation of cyclin E1.

Drug resistance has always been an important problem affecting the therapeutic effect of hepatocellular carcinoma (HCC). To investigate the potential role of lncRNA TTN-AS1 in HCC cells with sorafenib (SOR) resistance, and explore the underlying pathways, quantitative real time polymerase chain reaction (qRT-PCR) was used to test the expression of TTN-AS1 in HCC tissues and cells. Then, the expression of TTN-AS1 was down-regulated by shRNA, the activity changes, apoptosis and related protein expression in HCC cells with/without SOR treatment were observed in succession. Expression levels of the downstream target of TTN-AS1, miR-16-5p were studied by dual-luciferase binding assay, cell proliferation, and western blotting analysis. Nude mice models of human HCC with TTN-AS1 gene knockdown were established to observe the tumor growth. As the results revealed, TTN-AS1 silencing in HCC cells induced apoptosis by enhancing the sensitivity of cells to SOR, and the tumor in nude mice became smaller. The mechanism study showed that miR-16-5p was affected by TTN-AS1 sponge, up-regulated cyclin E1 expression, and regulated PTEN/Akt signaling pathway, thereby significantly alleviating the inhibition of apoptosis of HCC cells induced by TTN-AS1 gene. Collectively, our results provided TTN-AS1 as a potential therapeutic target for sorafenib resistance in HCC.

Upregulation of ARHGAP30 attenuates pancreatic cancer progression by inactivating the ß-catenin pathway.

BACKGROUND: Pancreatic cancer is a highly malignant gastrointestinal cancer that can widely metastasize during the early stage of disease, and it is associated with one of the worst prognoses among cancers. In this study, we aimed to investigate the function of Rho GTPase-activating protein 30 (ARHGAP30) in pancreatic cancer cells and thus propose a novel therapy for pancreatic cancer. METHODS: ARHGAP30 expression in tumor tissues from patients with pancreatic cancer as well as cell lines was detected using immunohistochemistry (IHC), real-time polymerase chain reaction, and western blotting. Cell proliferation, transwell, and apoptosis assays were performed and the levels of related proteins were determined after ARHGAP30 knockdown or overexpression. Additionally, in vivo experiments were performed on nude mice. RESULTS: ARHGAP30 expression was found to be significantly increased in tumor tissues from patients with pancreatic cancer as well as in pancreatic cancer cell lines. IHC and prognostic analyses indicated that patients with high ARHGAP30 expression had a good prognosis. ARHGAP30 overexpression significantly decreased pancreatic cancer cell proliferation and metastasis; promoted apoptosis; reduced ß-catenin, B-cell lymphoma 2 (Bcl-2), matrix metalloproteinase-2 (MMP2), and MMP9 expression; and increased Bcl-2-associated X protein (Bax) and cleaved caspase-3 expression. ARHGAP30 knockdown elicited the opposite effects. The effects of ARHGAP30 knockdown were potently attenuated by the ß-catenin inhibitor XAV939. ARHGAP30 knockdown-induced RHOA activity was potently attenuated by the RHOA inhibitor CCG1423. In vivo, ARHGAP30 overexpression significantly inhibited lung metastasis in nude mice and increased the survival of mice with lung metastases. CONCLUSIONS: Our findings indicate that ARHGAP30 may function as a tumor suppressor in pancreatic cancer progression by regulating the expression of related genes and the ß-catenin pathway.

Prognostic significance of red blood cell distribution width in gastrointestinal cancers: A meta-analysis.

BACKGROUND: Many publications showed red blood cell distribution width (RDW) might associate with the prognosis of gastrointestinal (GI) cancers, however, the agreement has not been reached because of controversial results. This meta-analysis aimed to explore the prognostic value of RDW in GI cancers. METHODS: Four common databases were comprehensively searched to look for relevant studies. The meta-analyses for overall survival (OS) and disease-free survival were performed using hazard ratio (HR) and 95% confidence interval (CI), and the meta-analyses for clinical parameters were conducted using odd ratio and 95% CI. RESULTS: A total of 13 studies involving with 3,509 patients with GI cancers were included into this study. The results showed, compared to patients with low RDW, patients with high RDW tended to have shorter OS (HR = 1.75, 95%CI = 1.57-1.94, P < .01) and disease-free survival (HR = 1.67, 95%CI = 1.39-2.00, P < .01). High RDW was associated with larger tumor size (P < .01), worse differentiation (P = .02), deeper invasion (P < .01), earlier lymph node metastasis (P < .01), more advanced clinical stage (P < .01) and higher carcinoembryonic antigen level (P < .01) when compared to low RDW. CONCLUSION: High RDW was significantly associated with worse prognosis of GI cancers, which could be regarded as a prognostic biomarker for GI cancers. More prospective studies with large sample size and long follow-up period should be carried out to determine the prognostic significance of RDW in GI cancers in future.

LncRNA UCA1 impacts cell proliferation, invasion, and migration of pancreatic cancer through regulating miR-96/FOXO3.

This study was expected to reveal the regulatory effects of lncRNA UCA1 on pancreatic cancer cell progression through targeting miR-96/FOXO3. Microarray analysis was carried out on 36 cases of pancreatic cancer tissues and 16 cases of adjacent tissues among them. Expression levels of lncRNA UCA1, miR-96, and FOXO3 in pancreatic cancer tissues and cell lines were determined by qRT-PCR. Expression levels of FOXO3 protein were determined by western blot. Cell viability, cell cycle and apoptosis, cell invasion and migration were detected by CCK-8, flow cytometry, and transwell assay, respectively. The colocalization relationship between lncRNA UCA1 and miR-96 was detected by RNA FISH. Whether UCA1 could target miR-96 and whether miR-96 could target FOXO3 3'UTR were verified by dual-luciferase reporter gene assay. High expression of lncRNA UCA1 and FOXO3 and low expression of miR-96 were shown in pancreatic cancer. Inhibition of UCA1 suppressed pancreatic tumor cell proliferation, colony formation, and metastasis, while inhibition of miR-96 promoted pancreatic cancer cell progression. FOXO3 was the downstream target gene of miR-96 and showed the opposite effects. LncRNA UCA1 promoted cell proliferation, invasion, migration and inhibited cell apoptosis of pancreatic cancer through down-regulating miR-96 and up-regulating FOXO3. © 2018 IUBMB Life, 70(4):276-290, 2018.

Study on mechanism about long noncoding RNA MALAT1 affecting pancreatic cancer by regulating Hippo-YAP signaling.

By investigating the migration and invasion ability in pancreatic cancer, this study probed into the lncRNA MALAT1 molecular mechanism on Hippo-YAP signaling. The expression of lncRNA MALAT1 in PC tissues and cells was detected by qRT-PCR and Western blot. The effect of si-MALAT1 on proliferation was determined by CCK-8 assay. Cell apoptosis, migration, and invasion were respectively detected by flow cytometry assay, wound healing assay, and transwell assay. Western blot and immunohistochemistry were successively used for detecting LATS1 and YAP1 expression in pancreatic cancer tissues. The microarray analysis determined that lncRNA MALAT1 in pancreatic cancer was highly expressed. LncRNA MALAT1 presented an extremely high expression level in pancreatic cancer tissues and cells. After transfected with si-MALAT1, the proliferation of AsPC-1 cells decreased, induce apoptosis of AsPC-1 cells, and migration and invasion ability were reduced. The tendency of LATS1 expression level was down-regulated and YAP1 show the opposite trend in the Hippo-YAP signaling. The in vivo assay was found that the tumor to be small in size and volume, and the expression of Ki-67 was decreased. High expression of lncRNA MALAT1 in PC disorder the proliferation, apoptosis, and migration and invasion ability via influence Hippo-YAP signaling pathway.

Prognostic role of long non-coding RNA TUG1 expression in various cancers: a meta-analysis.

Several studies were conducted to explore the prognostic role of long non-coding RNA taurine upregulated gene 1 (lncRNA TUG1) expression in various cancers, with contradictory. This study aims to summarize the prognostic role of lncRNA TUG1 expression in various cancers. Embase, PubMed and Cochrane Library were completely retrieved. The cohort studies focusing on the prognostic role of lncRNA TUG1 expression in various cancers were eligible. The endpoints were overall survival (OS) and clinicopathological parameters. 9 studies involving a total of 1,078 patients were identified. The results showed that high lncRNA TUG1 expression was obviously associated with worse OS when compared to the low lncRNA TUG1 expression (HR = 1.37, 95% CI = 1.07-1.76, P = 0.01; I2 = 85%). However, No distinct relationship was observed between the lncRNA TUG1 expression and age (OR = 0.99, 95% CI = 0.76-1.28, P = 0.92; I2 = 4%), gender (OR = 0.92, 95% CI = 0.70-1.22, P = 0.57; I2 = 0%), diameter (OR = 0.83, 95% CI = 0.34-2.01, P = 0.67; I2 = 85%), smoking (OR = 1.09, 95% CI = 0.37-3.21, P = 0.87; I2 = 73%), TNM stage (OR = 0.60, 95% CI = 0.25-1.43, P = 0.25; I2 = 86%) and lymph node metastasis (OR = 1.07, 95% CI = 0.47-2.45, P = 0.87; I2 = 86%). In conclusion, it was revealed that high lncRNA TUG1 expression is an unfavorable predictor of OS in patients with cancers, and lncRNA TUG1 expression is a promising prognostic biomarker for various cancers.

Prognostic value and preoperative predictors of microvascular invasion in solitary hepatocellular carcinoma ≤ 5 cm without macrovascular invasion.

OBJECTIVES: The aim of this study was to investigate the prognostic value and preoperative predictors of microvascular invasion (MVI) in solitary hepatocellular carcinoma (HCC) ≤ 5 cm without macrovascular invasion. METHODS: A total of 233 consecutive HCC patients underwent curative hepatectomy were included in our study. Independent risk factors influencing the prognosis were identified, and preoperative predictors for MVI were determined. RESULTS: Multivariate regression analysis identified ICG-R15, BCLC staging and MVI as independent risk factors for the overall survival rate. Type of resection and MVI were independent risk factors for the recurrence-free survival rate. Kaplan-Meier analysis showed the overall survival and recurrence-free survival rates in patients with MVI were significantly poorer than those in patients without MVI (P = 0.002 and P = 0.001). Anatomical resection obviously improved the overall survival and recurrence-free survival rates in patients with MVI compared with non-anatomical resection (P = 0.017 and P = 0.009). A prediction scoring system for MVI was built up according to the three independent predictors (tumor size > 3.5 cm, AFP > 200 ng/mL and GGT > 53 U/L). The prevalence of MVI in HCC patients with predictive score ≥ 2 was 58.3%, which was obviously higher than patients with predictive score < 2 (20.8%). CONCLUSIONS: MVI is associated with a poor prognosis in solitary HCC ≤ 5 cm after hepatectomy. Anatomical resection could improve the prognosis of HCC patients with MVI. The preoperative prediction scoring model has practical value for the prediction of MVI.

Development and validation of a novel predictive scoring model for microvascular invasion in patients with hepatocellular carcinoma.

PURPOSE: Microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) cannot be accurately predicted preoperatively. This study aimed to establish a predictive scoring model of MVI in solitary HCC patients without macroscopic vascular invasion. METHODS: A total of 309 consecutive HCC patients who underwent curative hepatectomy were divided into the derivation (n=206) and validation cohort (n=103). A predictive scoring model of MVI was established according to the valuable predictors in the derivation cohort based on multivariate logistic regression analysis. The performance of the predictive model was evaluated in the derivation and validation cohorts. RESULTS: Preoperative imaging features on CECT, such as intratumoral arteries, non-nodular type of HCC and absence of radiological tumor capsule were independent predictors for MVI. The predictive scoring model was established according to the ß coefficients of the 3 predictors. Area under receiver operating characteristic (AUROC) of the predictive scoring model was 0.872 (95% CI, 0.817-0.928) and 0.856 (95% CI, 0.771-0.940) in the derivation and validation cohorts. The positive and negative predictive values were 76.5% and 88.0% in the derivation cohort and 74.4% and 88.3% in the validation cohort. The performance of the model was similar between the patients with tumor size ≤5cm and >5cm in AUROC (P=0.910). CONCLUSIONS: The predictive scoring model based on intratumoral arteries, non-nodular type of HCC, and absence of the radiological tumor capsule on preoperative CECT is of great value in the prediction of MVI regardless of tumor size.

Inhibition of BDNF-AS Provides Neuroprotection for Retinal Ganglion Cells against Ischemic Injury.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) protects retinal ganglion cells against ischemia in ocular degenerative diseases. We aimed to determine the effect of BDNF-AS on the ischemic injury of retinal ganglion cells. METHODS: The levels of BDNF and BDNF-AS were measured in retinal ganglion cells subjected to oxygen and glucose deprivation. The lentiviral vectors were constructed to either overexpress or knock out BDNF-AS. The luciferase reporter gene assay was used to determine whether BDNF-AS could target its seed sequence on BDNF mRNA. The methyl thiazolyl tetrazolium assay was used to determine cell viability, and TUNEL staining was used for cell apoptosis. RESULTS: The levels of BDNF-AS were negatively correlated with BDNF in ischemic retinal ganglion cells. BDNF-AS directly targeted its complementary sequences on BDNF mRNA. BDNF-AS regulated the expression of BDNF and its related genes in retinal ganglion cells. Down-regulation of BDNF-AS increased cell viability and decreased the number of TUNEL-positive retinal ganglion cells under oxygen and glucose deprivation conditions. CONCLUSION: Inhibition of BDNF-AS protected retinal ganglion cells against ischemia by increasing the levels of BDNF.

Preoperative Evaluation of Malignant Perihilar Biliary Obstruction: Negative-Contrast CT Cholangiopancreatography and CT Angiography Versus MRCP and MR Angiography.

OBJECTIVE: The purpose of this study was to compare negative-contrast CT cholangiopancreatography (CTCP) and CT angiography (CTA) with MRCP and MR angiography (MRA) for the preoperative evaluation of malignant perihilar biliary obstruction. MATERIALS AND METHODS: Twenty-one patients with pathologically proven malignant perihilar biliary obstructions who had undergone both CT and MRI examinations were reviewed retrospectively. Two reviewers independently analyzed the two image sets-the negative-contrast CTCP and CTA images (i.e., CT set) and the MRCP and MRA images (i.e., MRI set)-in preoperatively evaluating the classification of malignant perihilar biliary obstruction, hepatic artery and portal vein invasion, nodal metastasis, and organ spread. The results were compared with surgical and pathologic records. RESULTS: For the classification of malignant perihilar biliary obstruction on the two image sets, the accuracy was not statistically significant (p = 1.000 for reviewer 1 and p = 0.500 for reviewer 2). For the evaluation of portal vein invasion, nodal metastasis, and organ spread, the accuracies were also not statistically significantly different (p = 0.335, 0.339, and 0.781 for reviewer 1; and p = 0.403, 0.495, and 0.325 for reviewer 2, respectively). In the assessment of hepatic artery status, the accuracy was statistically significant (p = 0.046 for reviewer 1 and p = 0.036 for reviewer 2). CONCLUSION: Compared with the MRI set, the CT set provides equivalent performance in assessing the classification of malignant perihilar biliary obstruction, portal vein involvement, nodal metastasis, and organ spread, but has higher accuracy in assessing arterial invasion.

GDC-0980-induced apoptosis is enhanced by autophagy inhibition in human pancreatic cancer cells.

Pancreatic cancer remains fatal to the fast majority of affected patients. Activation of phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway plays an important role in pancreatic cancer progression and chemo-resistance. In the present study, we examined the activity of GDC-0980, a novel class I PI3K/mTOR kinase inhibitor, against pancreatic cancer cells in vitro. GDC-0980 inhibited AKT-mTOR activation and pancreatic cancer cell (PANC-1 and Capan-1 lines) survival. In both cancer cell lines, GDC-0980 simultaneously activated apoptosis and autophagy, the latter was detected by p62 degradation, Beclin-1 upregulation and light chain 3B (LC3B) conversion from a cytosolic (LC3B-I) to a membrane-bound (LC3B-II) form. Autophagy inhibitors including 3-methyladenine, hydroxychloroquine, NH4Cl and bafilomycin A1 enhanced apoptosis and cytotoxicity by GDC-0980, such an effect was reversed by caspase inhibitors (z-VAD-FMK and z-ITED-FMK). Furthermore, knockdown of LC3B or Beclin-1 through siRNA increased GDC-0980-induced anti-pancreatic cancer cell activity. Thus, inhibition of autophagy sensitizes GDC-0980-induced anti-pancreatic cancer activity, suggesting a novel therapeutic strategy for GDC-0980 sensitization.

Cisplatin-induced non-apoptotic death of pancreatic cancer cells requires mitochondrial cyclophilin-D-p53 signaling.

The pancreatic cancer remains a fatal disease for the majority of patients. Cisplatin has displayed significant cytotoxic effects against the pancreatic cancer cells, however the underlying mechanisms remain inconclusive. Here, we found that cisplatin mainly induced non-apoptotic death of the pancreatic cancer cells (AsPC-1 and Capan-2), which was associated with a significant p53 activation (phosphorylation and accumulation). Further, activated p53 was found to translocate to mitochondria where it formed a complex with cyclophilin D (Cyp-D). We provided evidences to support that mitochondrial Cyp-D/p53 complexation might be critical for cisplatin-induced non-apoptotic death of pancreatic cancer cells. Inhibition of Cyp-D by its inhibitor cyclosporine A (CsA), or by shRNA-mediated knockdown suppressed cisplatin-induced pancreatic cancer cell death. Both CsA and Cyp-D knockdown also disrupted the Cyp-D/p53 complex formation in mitochondria. Meanwhile, the pancreatic cancer cells with p53 knockdown were resistant to cisplatin. On the other hand, HEK-293 over-expressing Cyp-D were hyper-sensitive to cisplatin. Interestingly, camptothecin (CMT)-induced pancreatic cancer cell apoptotic death was not affected CsA or Cyp-D knockdown. Together, these data suggested that cisplatin-induced non-apoptotic death requires mitochondria Cyp-D-p53 signaling in pancreatic cancer cells.

Performance and kap of army medical officers at the border area

Background: The combination medical between army and pepople in protection, healthcare for people and army in the whole country was a great policy of The Party and State. Objectives: Evaluate result of combination between armed forces in epidemic control and preventive medicine programs at mountainous and coastal areas of Thua Thien Hue in 2006. Studying knowledge, attitude, practice of army medical officers and men canvassed masses about epidemic control and preventive medicine programs. Subjects and method: Officers, men, army medical officers in 41 communes (28 coastal communes and 13 mountainous communes) of 5 district have combination medical between army and pepople. Using epidemiology method to description, analysis, cross-sectional study. Results: In 2006, home-flies spraying was carried out in 18 out of 20 markets; 1,030 all size restaurants and 18 residential areas of 5 districts. The number of chemically treated latrines in high epidemic areas was accounted fof 15,1%. A population-based latrine construction project was initiated to build 838 new latrines, contributing to minimize the invironmental pollution. 9,17% of waterwells and water tanks were hygienically treated; 11,434 people used clean water source; and 46,436 people washed their hands with soap. Studying knowledge, attitude, practice on preventive medicine programs of army medical officers showed very good results. Conclusion: The combination medical between army and pepople in preventive medicine, epidemic control gave wide efficiency for mountainous and coastal communes of Thua Thien Hue. It actively supported for Health station of 28 coastal communes and 13 mountainous communes in preventive medicine work.