Hepatitis B virus promotes proliferation and metastasis in male Chinese hepatocellular carcinoma patients through the LEF-1/miR-371a-5p/SRCIN1/pleiotrophin/Slug pathway.

Hepatocellular carcinoma (HCC) is a male-dominant cancer. Several factors may contribute to the gender difference. Recent investigations have reported that miRNAs are involved in sex-linked signaling pathways and play a critical role in the molecular pathogenesis of hepatitis B virus (HBV)-related HCC. Therefore, we speculated that some of these miRNAs might contribute to the gender differences observed in HBV-related HCC. Our results showed that miR-371a-5p was significantly upregulated in tumor tissue and serum from HCC patients and that the expression level of miR-371a-5p was related to HBV infection, sexuality, TNM stage, adjacent organ invasion and microvascular invasion. Moreover, a high level of miR-371a-5p expression predicted poor overall survival of HCC patients, and in vitro and in vivo studies revealed that the overexpression of miR-371a-5p promoted proliferation and metastasis. Mechanistic investigations suggested that miR-371a-5p was upregulated by HBV and testosterone through LEF-1. SRCIN1 was a direct target of miR-371a-5p and reversed the effects of miR-371a-5p on HCC tumorigenesis. Our results also revealed that SRCIN1 negatively regulated the expression of PTN by inhibiting the activity of NF-κB. As a hepatocyte growth factor, PTN promoted EMT-induced metastasis in vitro and in vivo through the AKT/Slug pathway. These data strongly suggested that the upregulation of miR-371a-5p played an important role in HBV-related HCC. Through the LEF-1/miR-371a-5p/SRCIN1/PTN/Slug pathway, HBV and testosterone promote the proliferation and metastasis of hepatoma cells, especially in male patients with HBV-related HCC.

Pleiotrophin, a target of miR-384, promotes proliferation, metastasis and lipogenesis in HBV-related hepatocellular carcinoma.

Hepatitis B virus (HBV) infection plays a crucial role and is a major cause of hepatocellular carcinoma (HCC) in China. microRNAs (miRNAs) have emerged as key players in hepatic steatosis and carcinogenesis. We found that down-regulation of miR-384 expression was a common event in HCC, especially HBV-related HCC. However, the possible function of miR-384 in HBV-related HCC remains unclear. The oncogene pleiotrophin (PTN) was a target of miR-384. HBx inhibited miR-384, increasing PTN expression. The PTN receptor N-syndecan was highly expressed in HCC. PTN induced by HBx acted as a growth factor via N-syndecan on hepatocytes and further promoted cell proliferation, metastasis and lipogenesis. PTN up-regulated sterol regulatory element-binding protein 1c (SREBP-1c) through the N-syndecan/PI3K/Akt/mTORC1 pathway and the expression of lipogenic genes, including fatty acid synthesis (FAS). PTN-mediated de novo lipid synthesis played an important role in HCC proliferation and metastasis. PI3K/AKT and an mTORC1 inhibitor diminished PTN-induced proliferation, metastasis and lipogenesis. Taken together, these data strongly suggest that the dysregulation of miR-384 could play a crucial role in HBV related to HCC, and the target gene of miR-384, PTN, represents a new potential therapeutic target for the prevention of hepatic steatosis and further progression to HCC after chronic HBV infection.

Helicobacter pylori promotes invasion and metastasis of gastric cancer cells through activation of AP-1 and up-regulation of CACUL1.

Infection with Helicobacter pylori is important in the development and progression of gastric cancer. However, the mechanisms that regulate this activation in gastric tumors remain elusive. CACUL1 has been cloned and identified as a novel gene that is expressed in many types of cancer and is involved in cell cycle regulation and tumor growth. The current study aimed to examine the expression of CACUL1 in gastric cancer samples and analyze its correlation with H. pylori infection. We found that CACUL1 was highly expressed in gastric cancer tissues and negatively correlated with gastric cancer differentiation and TNM stage. In addition, CACUL1 expression was high in H. pylori-infected tissues compared with H. pylori non-infected tissue. We found that H. pylori could up-regulate CACUL1 expression through activating protein 1. The up-regulation of CACUL1 expression could promote matrix metalloproteinase 9 and Slug expression to increase invasion and metastasis of tumor cells. These results suggested that H. pylori-triggered CACUL1 production occurred in an activating protein 1-dependent manner and regulated matrix metalloproteinase 9 and Slug expression to affect the invasion and metastasis of tumor cells. Therefore, CACUL1 is a potential therapeutic target for the treatment of aggressive gastric cancer.

The deoxycholic acid targets miRNA-dependent CAC1 gene expression in multidrug resistance of human colorectal cancer.

There is evidence indicating that bile acid is a promoter of colorectal cancer. Deoxycholic acid modifies apoptosis and proliferation by affecting intracellular signaling and gene expression. We are interested in revealing the relationship between deregulated miRNAs and deoxycholic acid in colorectal cancer development. We found that miR-199a-5p was expressed at a low level in human primary colonic epithelial cells treated with deoxycholic acid compared with control, and miR-199a-5p was significantly down-regulated in colorectal cancer tissues. The miR-199a-5p expression in colorectal cancer cells led to the suppression of tumor cell growth, migration and invasion. We further identified CAC1, a cell cycle-related protein expressed in colorectal cancer, as a miR-199a-5p target. We demonstrated that CAC1 is over-expressed in malignant tumors, and cellular CAC1 depletion resulted in cancer growth suppression. HCT-8 cells transfected with a miR-199a-5p mimic or inhibitor had a decrease or increase in CAC1 protein levels, respectively. The results of the luciferase reporter gene analysis demonstrated that CAC1 was a direct miR-199a-5p target. The high miR-199a-5p expression and low CAC1 protein expression reverse the tumor cell drug resistance. We conclude that miR-199a-5p can regulate CAC1 and function as a tumor suppressor in colorectal cancer. Therefore, the potential roles of deoxycholic acid in carcinogenesis are to decrease miR-199a-5p expression and/or increase the expression of CAC1, which contributes to tumorigenesis in patients with CRC. These findings suggest that miR-199a-5p is a useful therapeutic target for colorectal cancer.

Expression of the newly identified gene CAC1 in the hippocampus of Alzheimer's disease patients.

Alzheimer's disease (AD), the most common form of senile dementia, is associated with neurodegeneration. The development of Alzheimer's disease is related to abnormalities of cell cycle regulation. Preliminary work showed that a novel gene, CAC1, was highly expressed in tumors and had an oncogene-like function related to cell cycle regulation. The pathogenesis of AD is still incompletely understood. In this study, we measured the expression level of CAC1 in the hippocampus of AD patients to explore the involvement of CAC1 in the development of AD. Our findings showed that the expression level of CAC1 in the hippocampus of AD patients was significantly lower than that of normal controls. The reduction of CAC1 expression did not affect tau/p-tau-396, amyloid precursor protein or apolipoprotein E4 in the in vitro model. A reduction of cyclin E was detected after a CAC1-knockdown. Interestingly, we found that the knockdown of CAC1 by RNAi led to an increase in oxidative stress and the level of p53 protein in SHSY-5Y cells. The expression of CAC1 in SHSY-5Y cells protected the cells from apoptosis induced by Aß toxicity or oxidative stress. These results established that CAC1 is an important factor for the protection of cells against Aß toxicity and oxidative stress.

Pleiotrophin is a potential colorectal cancer prognostic factor that promotes VEGF expression and induces angiogenesis in colorectal cancer.

PURPOSE: Pleiotrophin (PTN) is an important developmental secretory cytokine expressed in many types of cancer and involved in angiogenesis and tumor growth; however, the significance of PTN expression in colorectal cancer (CRC) has not been established. METHODS: Immunohistochemistry, western blot, and enzyme-linked immunosorbent assay were used to detect PTN expression in CRC patients. The relationship between PTN expression and clinicopathological characteristics and survival time was statistically analyzed, and the relationship between PTN and vascular endothelial growth factor (VEGF) in tumor angiogenesis was further analyzed. RESULTS: Of CRC tissues, 74.70% (62/83) stained positive, with a strong positive ratio of 60.24% (50/83). The expression of PTN in CRC tissues was much higher than in normal colorectal tissues. PTN serum levels in CRC patients (mean = 254.59 ± 261.76 pg/ml) were significantly higher than those of normal volunteers (mean = 115.23 ± 79.53 pg/ml; p < 0.001). PTN expression was related to CRC differentiation and TNM staging. High level of PTN is a predictor of a poor prognosis and high expression of PTN is accompanied by high expression of VEGF in CRC patients. Investigation of the relationship between PTN and VEGF revealed that PTN, through the PTN/RPTPß/ζ signaling pathway, increased tyrosine phosphorylation of ß-catenin, leading to an increase in VEGF. CONCLUSIONS: Our study identifies PTN as an essential growth factor for CRC. PTN promotes VEGF expression and cooperates with VEGF in promoting CRC angiogenesis. PTN could serve as a prognostic factor for this cancer. Considering that PTN shows very limited expression in normal tissue, it may represent an attractive new target for CRC therapy.

Needlestick injuries among nursing students in China.

OBJECTIVES: To describe and characterize the rates and the nature of needlestick injuries among nursing students in China. METHODS: A questionnaire was delivered to 248 randomly selected nursing students from seven training hospitals to obtain information relevant occupational needlestick injuries. RESULTS: A total of 1144 incidents of needlestick injuries were reported among the 246 nurses during the time period of internship. The overall rate of needlestick injuries among these nurses was 100%, according to this survey. Insufficient awareness of occupational safety and limited work experience with handling needlestick injuries in these nurse students were significantly reported. In addition, when stratified by departments, the highest rate of needlestick injuries was seen in the surgery department. The occurrence of needlestick injuries is significantly related to clinical practice behaviors. CONCLUSIONS: Needlestick injuries are commonly reported in nursing students in China. Enhanced awareness of occupational safety in nursing students is expected to reduce the risk of needlestick injuries.

[Expression of dihydropyrimidine dehydrogenase in human colorectal carcinoma and its clinical implications].

OBJECTIVE: The study was to explore the dihydropyrimidine dehydrogenase (DPD) expression level in human colorectal carcinoma and its clinical implications. METHODS: Fifty-three patients with colorectal carcinoma were detected by immunohistochemical stain. These patients had undergone radical surgical treatment in the First Hospital of Xi'an Jiaotong University and had been followed up for 5 years after the operation. cases Twenty-two had received 5-fluorouracil-based adjuvant chemotherapy. RESULTS: DPD expression was predominantly observed in the cytoplasm of the tumor cells, and also partly in the nucleus. The positive rate of DPD expression was 73.58% (39/53). DPD expression in patients with different histopathology was obviously different (P < 0.05). There was no significant correlation between the expression of DPD and the efficacy of chemotherapy. By Kaplan-Meier methods, the survival patients with of negative DPD expression was longer than those with positive DPD expression, and then five-year survival rates were 12.97% and 42.86%, respectively (P < 0.05). The prognosis of patients with positive DPD expression was significantly poorer outcome than that of patients with negative DPD expression. CONCLUSION: These findings suggest that DPD expression might be one of the important prognostic parameters for colorectal cancer patients.

B7 molecule mRNA expression in colorectal carcinoma.

AIM: To observe the status of tumor-associated B(7) molecule mRNA expression in human colorectal cancer tissue by in situ hybridization. METHODS: The mRNA expression patterns of cancer-associated B(7-1),B(7)H(1),B(7)H(2),ICOS in 22 specimens of human colorectal cancer tissue were monitored by in situ hybridization (ISH) with digoxin-labeled oligonucleotide probes. RESULTS: B(7-1),B(7)H(1),B(7)H(2),ICOS mRNA were detected in both cancer cells and tumor infiltrating lymphocytes (TIL). The mRNA expression level of these molecules in tumor cells was higher than that in TIL (0.76+/-0.54 - 1.62+/-0.82 vs 0.38+/-0.19 - 0.65+/-0.33, P<0.001). There was no relationship between expression level of tested B(7) family molecules and patients' sex, age, differentiation status of cancer and regional lymph node metastasis. CONCLUSION: Th2 cytokine predominant in tumor microenvironment might be related to the expression of B(7)H(1),B(7)H(2) co-signal molecules in tumor cells and TIL.