Metabolism-related lncRNAs signature to predict the prognosis of colon adenocarcinoma.

BACKGROUND: Cell metabolism and long noncoding RNA (lncRNA) played crucial roles in cancer development. However, their association in colon adenocarcinoma (COAD) remains unclear. METHODS: The COAD gene expression data and corresponding clinical data were retrieved from The Cancer Genome Atlas (TCGA) database. Differential expression of metabolic genes and lncRNA were identified by comparing tumor and normal colon tissues. Pearson correlation analysis was performed to identify metabolism-associated lncRNA. COAD patients were divided into training cohort and validation cohort by randomization. Then, a univariate Cox regression analysis was introduced to evaluate the correlations between metabolism-related lncRNAs and overall survival (OS) of the patients in the training cohort. The least absolute shrinkage and selection operator (LASSO) method was introduced to determine and establish a prognostic prediction model. Subsequently, survival analysis, receiver operating characteristic (ROC) curve analysis, and Cox regression analysis were generated to estimate the prognostic role of the LncRNA risk score in training, validation, and entire cohorts. RESULTS: We identified 152 differentially expressed metabolism-associated lncRNAs (MRLncRNAs). A prognostic prediction model involving four metabolism-related lncRNAs were established using LASSO. In each cohort, COAD patients in the high-risk group had worse OS compared to those in the low-risk group. The ROC analyses demonstrated that the lncRNA signature performed well in predicting OS. Uni- and multivariate analysis indicated that the lncRNA signature as an independent prognostic factor. Furthermore, a correlation analysis demonstrated that LINC01138 was the most closely lncRNA related to metabolic genes. In vitro assays demonstrated that LINC01138 affects tumor progression in COAD. CONCLUSIONS: In summary, we established a metabolism-associated lncRNAs model to predict the prognosis in COAD patients.

Aspirin attenuates liver fibrosis by suppressing TGF­ß1/Smad signaling.

Aspirin reduces the liver fibrosis index and inflammation in patients and rats. However, the specific mechanism underlying the effects of aspirin are yet to be elucidated. The present study aimed to investigate the effects of aspirin on thioacetamide (TAA)­induced liver fibrosis in rats and hepatic stellate cells (HSCs) via the TGF­ß1/Smad signaling pathway. Liver fibrosis was induced in Sprague Dawley rats by intraperitoneal injection of 200 mg/kg TAA twice weekly for 8 weeks. Aspirin (30 mg/kg) was administered to rats by gavage once every morning over a period of 8 weeks. Masson's trichrome and H&E staining were used to detect and analyze the pathological changes in liver tissues. Western blot analysis and immunohistochemistry were applied to determine the protein expression levels of α­smooth muscle actin (α­SMA), collagen I, TGF­ß1, phosphorylated (p)­Smad2 and p­Smad3. In addition, reverse transcription­quantitative PCR was performed to detect the mRNA expression levels of α­SMA, collagen type I α 1 chain (COL1A1) and TGF­ß1. The results demonstrated that treatment with aspirin significantly reduced the serum levels of alanine aminotransferase, aspartate aminotransferase and hydroxyproline in the TAA + aspirin compared with that in the TAA group. In the rat liver fibrosis model, pathological changes in liver tissues were improved following treatment with aspirin. Similarly, a marked decrease was observed in protein expression levels of α­SMA, collagen I, TGF­ß1, p­Smad2 and p­Smad3. Furthermore, aspirin administration decreased the mRNA levels of α­SMA, COL1A1 and TGF­ß1. In addition, HSCs were treated with different concentrations of aspirin (10, 20 and 40 mmol/l), and the protein expression levels of α­SMA, collagen I, TGF­ß1, p­Smad2 and p­Smad3 were reduced in a dose­dependent manner. Overall, the present study showed that aspirin attenuated liver fibrosis and reduced collagen production by suppressing the TGF­ß1/Smad signaling pathway, thus revealing a potential mechanism of aspirin in the treatment of liver fibrosis.

Wogonoside promotes apoptosis in gastric cancer AGS and SGC-7901 cells through induction of mitochondrial dysfunction and endoplasmic reticulum stress.

Wogonoside (Wg), a natural flavonoid, has anticancer effects against several human cancers. The purpose of the present study was to investigate the antitumor effects and underlying mechanisms of Wg on gastric cancer (GC) cell lines. We report that Wg treatment inhibited cell viability and induced apoptosis in human GC cell lines AGS and SGC-7901, and also retarded GC tumor growth in xenograft mice in vivo. We also found that the Wg exerted its antitumor effects against GC cells via induction of reaction oxygen species accumulation, mitochondrial dysfunction, and endoplasmic reticulum stress. Furthermore, C/EBP homologous protein knockdown inhibited apoptosis and increased the viability of Wg-treated GC cells. Our findings may facilitate the development of novel therapeutic agents for the treatment of GC.

Antiviral Drug Ribavirin Targets Thyroid Cancer Cells by Inhibiting the eIF4E-ß-Catenin Axis.

BACKGROUND: Although eukaryotic translation initiation factor 4E (eIF4E) is important in cancer development and progression, its role in thyroid cancer is not well understood. Ribavirin, an anti-viral drug, has been identified as an eIF4E inhibitor. Herein, we investigated the effects of ribavirin on thyroid cancer and its molecular mechanisms of action. MATERIALS AND METHODS: The effects of ribavirin on thyroid cancer was investigated using in vitro cellular assays and in vivo xenograft mouse model. The mechanism of its action on eIF4E-ß-catenin axis was examined using genetic and biochemical approaches. RESULTS: We show that ribavirin inhibited proliferation and induced apoptosis in the thyroid cancer cell lines 8505C and FTC-133. Ribavirin inhibited thyroid cancer growth in a xenograft mouse model. Ribavirin also sensitized thyroid cancer's response to paclitaxel. Mechanistically, ribavirin suppressed eIF4E phosphorylation and overexpression of its wildtype and phosphor-mimetic form (S209D) but not of the non-phosphorylatable form (S209A), which rescued the inhibitory effects of ribavirin in thyroid cancer cells. We further demonstrated that ribavirin suppressed phosphorylation and activities of ß-catenin and its subsequent gene transcriptional expression. ß-Catenin overexpression rescued the effects of ribavirin in thyroid cancer cells. Importantly, we show that eIF4E regulated ß-catenin and that the regulation depended on phosphorylation at S209. The in vivo inhibitory effects of ribavirin on phosphorylation of eIF4E and ß-catenin were also observed in thyroid tumor. CONCLUSIONS: Our data clearly demonstrate that ribavirin acts on thyroid cancer cells by inhibiting eIF4E/ß-catenin signaling. Our findings suggest that ribavirin has the potential to be repurposed for thyroid cancer treatment and also highlight the therapeutic value of inhibiting eIF4E-ß-catenin in thyroid cancer.

Perforation of small bowel caused by Schistosoma japonicum: a case report.

A 67-year-old man from Jingzhou was admitted to the First Hospital Affiliated to Yangtze University in July 2013 with sudden onset of abdominal pain with dizziness for 12 h. The patient had sign of peritoneal irritation. Ultrasonography of the abdomen and pelvis showed hepatic fibrosis due to schistosomiasis. Computed tomography showed free gas in the peritoneal cavity. Plain abdominal radiography showed bilateral subdiaphragmatic accumulation of gas, perforation of the viscus, and radio-opacity in the left renal area. The patient underwent emergency exploratory laparotomy. At laparotomy, a moderate amount of muddy yellow pus was found in the intra-abdominal cavity. At the junction of the jejunum and ileum, about 250 cm from Treitz's ligament, there was an about 10-cm length of inflamed small bowel with perforation (3 mm in diameter) along the mesenteric border at the middle of the lesion. The patient underwent resection of the affected intestinal segment, along with end-to-end intestinal anastomosis. Histopathological examination revealed mucosal necrosis and hemorrhage with a large number of infiltrating eosinophils and neutrophils, and acute submucosal inflammation with a large number of infiltrating eosinophils and neutrophils associated with Schistosoma japonicum (S. japonicum) eggs. No intravascular adult parasite was found. Postoperatively, the patient was treated with praziquantel (30 mg/kg daily) for 4 d. The patient progressed well. To the best of our knowledge, this is the first case of small bowel perforation associated with eggs of S. japonicum.

The effect of targeted magnetic nanopaticles on hepatoma and the expression of bcl-2/bax protein.

The effect of targeted magnetic nanoparticles on hepatoma and the underlying mechanism were examined. Nude mice transplanted with a human hepatoma cell line (HepG2 cells) were randomized into 5 groups, including: (1) group A, receiving normal saline, (2) group B, receiving 5-fluorouracil (5-Fu), (3) group C, receiving magnetic nanoparticles containing 5-Fu, (4) group D, consisting of treatment with magnetic nanoparticles containing 5-Fu and inside magnetic field and (5) group E, receiving pure magnetic nanoparticles and inside magnetic field. Morphological features of transplanted tumors in mice in each group were observed under transmission electron microscope (TEM). The expression of bcl-2/bax protein was immunohistochemically detected by SABC method. The results showed that a large number of apoptotic tumor cells were found in group B and group D under TEM. The expression of bcl-2 protein was significantly decreased and the expression of bax protein increased significantly in both group B and D as compared with those in group A, C and E (P<0.01 for all). The decrease in bcl-2 and the increase in bax were more in group D as compared with group B (P<0.01). It is concluded that the targeted magnetic nanoparticles containing 5-Fu can improve the chemotherapeutic effect of 5-Fu by decreasing bcl-2 expression, increasing bax expression and inducing apoptosis of the liver cancer cells.

Correlation of aPKC-iota and E-cadherin expression with invasion and prognosis of cholangiocarcinoma.

BACKGROUND: The abnormal expression of atypical protein kinase C-iota (aPKC-iota) subtype and E-cadherin play important roles in tumor occurrence and progression. This study was designed to investigate the correlation of expression of aPKC-iota and E-cadherin with the clinicopathological characteristics and prognosis of cholangiocarcinoma, and to analyze the molecular mechanisms of invasion and metastasis of the tumor. METHODS: EnVision immunohistochemistry was used to detect the expression of aPKC-iota and E-cadherin in 9 specimens of benign bile duct tissues, 35 specimens of cholangiocarcinoma and 6 specimens of metastatic cholangiocarcinoma. The relationship of the expression with clinicopathological characteristics, invasion and prognosis of cholangiocarcinoma was analyzed. A multivariate regression analysis was made of these data by the Cox proportional hazard model. RESULTS: The positive expression level of aPKC-iota in cholangiocarcinoma was remarkably higher than that in benign bile duct tissues (68.6% vs. 11.1%, P=0.006), but the expression level of E-cadherin was lower in cholangiocarcinoma than in benign bile duct tissues (37.1% vs. 88.9%, P=0.016). Correlation analysis revealed that the expression of aPKC-iota was positively related to tumor differentiation and invasion, whereas that of E-cadherin was entirely the contrary. Moreover, there was a negative relationship between the expression of aPKC-iota and that of E-cadherin (r=-0.287, P<0.05). Univariate analysis showed that the overall survival rate of the group with a higher expression of aPKC-iota in cholangiocarcinoma was remarkably lower than that of the group with a lower expression (P<0.01); multivariate analysis revealed that the expressions of aPKC-iota and E-cadherin are important prognostic factors for cholangiocarcinoma (P<0.05). CONCLUSIONS: The expressions of aPKC-iota and E-cadherin may reflect the differentiation and invasive potential of cholangiocarcinoma. aPKC-iota and E-cadherin may be independent prognostic factors and, when used in combination with clinicopathological characteristics, may increase the accuracy in predicting the prognosis of patients with cholangiocarcinoma. As a polar regulative associated protein, aPKC-iota may play an important role in the invasion and metastasis of cholangiocarcinoma.

The Effect of Targeted Magnetic Nanopaticles on Hepatoma and the Expression of bcl-2/bax Protein / 华中科技大学学报（医学）（英德文版）

The effect of targeted magnetic nanoparticles on hepatoma and the underlying mechanism were examined. Nude mice transplanted with a human hepatoma cell line (HepG2 cells) were randomized into 5 groups, including: (1) group A, receiving normal saline, (2) group B, receiving5-fluorouracil (5-Fu), (3) group C, receiving magnetic nanoparticles containing 5-Fu, (4) group D,consisting of treatment with magnetic nanoparticles containing 5-Fu and inside magnetic field and (5)group E, receiving pure magnetic nanoparticles and inside magnetic field. Morphological features of transplanted tumors in mice in each group were observed under transmission electron microscope(TEM). The expression of bcl-2/bax protein was immunohistochemically detected by SABC method.The results showed that a large number of apoptotic tumor cells were found in group B and group D under TEM. The expression of bcl-2 protein was significantly decreased and the expression of bax protein increased significantly in both group B and D as compared with those in group A, C and E(P＜0.01 for all). The decrease in bcl-2 and the increase in bax were more in group D as compared with group B (P＜0.01). It is concluded that the targeted magnetic nanoparticles containing 5-Fu can improve the chemotherapeutic effect of 5-Fu by decreasing bcl-2 expression, increasing bax expression and inducing apoptosis of the liver cancer cells.

[Expression and significance of aPKC-iota and E-cadherin in cholangiocarcinoma].

BACKGROUND & OBJECTIVE: Studies showed that the abnormal expression of atypical protein kinase C iota subtype (aPKC-iota) and E-cadherin plays an important role in tumor genesis and progression. This study was to investigate the expression of aPKC-iota and E-cadherin in cholangiocarcinoma, and analyze molecular mechanisms of the invasion and metastasis of cholangiocarcinoma. METHODS: The expression of aPKC-iota and E-cadherin in 9 specimens of benign bile duct tissues and 35 specimens of cholangiocarcinoma was detected by EnVision immunohistochemistry, and their correlations to the clinicopathologic characteristics and invasion of cholangiocarcinoma were analyzed. RESULTS: The positive rate of aPKC-iota was significantly higher in cholangiocarcinoma than in benign bile duct tissues (68.6% vs. 11.1%, P = 0.006), while the positive rate of E-cadherin was significantly lower in cholangiocarcinoma than in benign bile duct tissues (37.1% vs. 88.9%, P = 0.016). aPKC-iota expression was negatively correlated to E-cadherin expression (r = -0.287, P < 0.05). aPKC-iota expression was positively and E-cadherin expression was negatively correlated to the differentiation and invasion of cholangiocarcinoma (P < 0.05). CONCLUSIONS: The expression of aPKC-iota and E-cadherin may reflect the differentiation and invasive potential of cholangiocarcinoma. As a polar regulation-associated protein, aPKC-iota may play a role in the invasion and metastasis of cholangiocarcinoma.

Effect of targeted magnetic nanoparticles containing 5-FU on expression of bcl-2, bax and caspase 3 in nude mice with transplanted human liver cancer.

AIM: To investigate the anti-tumor effect and mechanisms of magnetic nanoparticles targeting hepatocellular carcinoma. METHODS: Human hepatocellular carcinoma was induced in nude mice, and the mice were randomly divided into group A receiving normal saline, group B receiving magnetic nanoparticles containing 5-fluorouracil (5-FU), group C receiving 5-FU, and group D receiving magnetic nanoparticles containing 5-FU with a magnetic field built in tumor tissues. The tumor volume was measured on the day before treatment and 1, 4, 7, 10 and 13 d after treatment. Tumor tissues were isolated for examination of the expression of bcl-2, bax and caspase 3 by immunohistochemical method, reverse transcription polymerase chain reaction and Western blotting. RESULTS: The tumor volume was markedly lower in groups C and D than in groups A and B (group C or D vs group A or B, P<0.01). The volume was markedly lower in group D than in group C (P<0.05). The expression of protein and mRNA of bcl-2 was markedly lower in groups C and D than in groups A and B (group C or D vs group A or B, P<0.01), and was markedly lower in group D than in group C (P<0.01). The expression of bax and caspase 3 in groups C and D was significantly increased, compared with that in groups A and B (P<0.01). CONCLUSION: The targeted magnetic nanoparticles containing 5-FU can improve the chemotherapeutic effect of 5-FU against hepatocellular carcinoma by decreasing the expression of bcl-2 gene, and increasing the expression of bax and caspase 3 genes.

Roles of protein kinase C and fructose in hepatic injury caused by obstructive jaundice.

The regulating mechanism in hepatic injury caused by obstructive jaundice (OJ) was examined in this study. Rat hepatocytes were harvested by in situ collagenase perfusion and subjected to primary culture. The heptocytes were pre-treated with various concentrations of protein kinase C (PKC) agonist PMA and its inhibitor chelerythrine and cultured for 20 min. After the treatment, 50 micromol/L glycochenodeoxycholate (GCDC) was added and the cells were cultured for an additional 24 h. Cells were then detected by flow cytometry (FCM) and TUNEL. After hepatocytes were treated with different concentrations of fructose and 100 microM GCDC, the cells were examined by FCM and TUNEL. Experimental obstructive jaundice (BDL) was induced by double ligation of the bile duct. After BDL, the rats were fed with or without fructos and sacrificed 3, 7, 14 and 21 days after the ligation. The apoptotic status was observed in liver of all rats with TUNEL and PKC protein in liver of OJ was studied by immunohistochemical method. Our results showed that PMA increased GCDC-induced apoptosis and chelerythrine decreased GCDC-induced apoptosis in a concentration-dependent manner. After the treatment with fructose of different concentrations, 100 microM GCDC decreased the apoptotic rate and the apoptotic rate decreased with the increase of fructose concentration. The apoptotic rate of liver was related to the time of OJ. Without the treatment of fructose, PKC and apoptosis index (AI) were highest 14 days after the bile duct ligation. With the treatment of fructose, apoptosis index (AI) and PKC were decreased from the 14th day after the bile duct ligation. It is concluded that PKC is involved in the regulation of apoptosis in the liver cells with OJ and plays important roles in the development and progression of liver injury caused by OJ. Fructose can protect hepatocytes in the bile salt-induced apoptosis by regulating PKC.