Long non-coding RNA DLX6-AS1 silencing inhibits malignant phenotypes of gastric cancer cells.

It has been revealed that long non-coding RNAs (lncRNAs) serve a key role in various malignancies, including gastric cancer (GC). In the present study, the expression and function of lncRNA distal-less homeobox 6 antisense 1 (DLX6-AS1) in GC was investigated. The data revealed that the expression of DLX6-AS1 was significantly upregulated in GC tissues compared with adjacent paired noncancerous tissues. Furthermore, the expression of DLX6-AS1 was higher in advanced GC tissue samples (III/IV) compared with the expression in early-stage samples (I/II). Furthermore, the current study demonstrated that a high expression of DLX6-AS1 was significantly associated with advanced clinical stage, lymph node metastasis and distant metastasis. Compared with patients with a low DLX6-AS1 expression, DLX6-AS1 expression in patients with GC was associated with decreased survival. In vitro experimental data indicated that DLX6-AS1 was upregulated in GC cell lines and that the inhibition of DLX6-AS1 markedly reduced GC cell proliferation, colony formation, cell cycle progression, migration and invasion. Further investigation revealed that knockdown of DLX6-AS1 inhibited EMT in GC cells. In summary, the present study demonstrated that lncRNA DLX6-AS1 was upregulated and serves an oncogenic role in GC, indicating that DLX6-AS1 may be a novel therapeutic target for GC treatment.

Aberrant CEACAM19 expression is associated with metastatic phenotype in penile cancer.

OBJECTIVE: A greater knowledge of the mechanisms of the pathogenesis of penile cancers may assist in the development of more tailored targeted therapy. Herein, we aimed to evaluate the expression of CEACAM19 in penile cancer and to explore its regulatory mechanisms. MATERIAL AND METHODS: This retrospective study enrolled 64 penile cancer patients who underwent penectomy between 2011 and 2015. CEACAM19 expression in tissues was detected by immunohistochemistry, which was analyzed in association with clinicopathological parameters. Kaplan-Meier analysis was performed to evaluate the relationship between CEACAM19 expression and prognosis of patients with penile cancer. Cell Counting Kit-8 assay and clonogenic assay were used to evaluate the cell viability and tumorigenic potential of penile cancer cell line, respectively; wound healing assay and transwell invasion assay were conducted to evaluate the effect of CEACAM19 depletion on cell migration and invasion in penile cancer cells; CEACAM19 protein expression was analyzed by Western blotting. Culture supranatant matrix metalloproteinase 2/9 (MMP2/9) was detected by ELISA. RESULTS: CEACAM19 was differentially expressed in non-cancerous and penile cancer tissues. Over-expression of CEACAM19 was significantly associated with nodal and distant metastasis, and predicted unfavorable cancer-specific survival in penile cancer. Depletion of CEACAM19 expression suppressed cell proliferation, reduced colony formation, and attenuated cell migration and invasion in Penl1 cells. Furthermore, knockdown of CEACAM19 expression attenuated the levels of p-Smad2/3 and reduced secretion of MMP2/9 in Penl1 cells. The effects of CEACAM19 might result from its function in regulating the Smad2/3 activation, as inhibition on Smad2/3 activation suppressed cell migration and invasion and reduced MMP2/9 secretion in Penl1 cells. CONCLUSION: Over-expression of CEACAM19 might serve as a potential prognostic biomarker for clinical management of penile cancer. Strategies targeting CEACAM19-regulated signaling pathways may have a therapeutic benefit in penile cancer.

Overexpression of ID1 promotes tumor progression in penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) occurs more frequently in developing countries, and is commonly diagnosed at an advanced stage with an unfavorable prognosis. At present, few biomarkers for PSCC have been identified and used in clinical practice. Aberrant expression of inhibitor of DNA binding 1 (ID1) has been suggested as a potential regulator of tumor progression in various types cancer. Herein, we evaluated ID1 expression in PSCC and analyzed its association with the clinicopathological parameters of PSCC. Our findings indicated that ID1 overexpression is associated with histological subtype and lymph node metastasis. Kaplan­Meier survival analysis showed that the overexpression of ID1 is associated with unfavorable cancer­specific survival. In Cox proportional hazard models, ID1 overexpression was found to be an independent predictor of cancer­specific survival. Furthermore, we investigated the function of ID1 in PSCC using a PSCC cell line Penl1. Silencing of ID1 expression retarded cell growth, inhibited clonogenesis, and attenuated cell migration and invasion in Penl1 cells. ID1 may regulate key oncogenic and metastasis­related molecules, as depletion of ID1 expression affected the levels of p­AKT, p16, PTEN and cleaved caspase­3, and reduced MMP2/9 secretion in Penl1 cells. Nevertheless, the mRNA expression of p16 and PTEN increased following ID1 knockdown, suggesting that ID1 may repress p16 and PTEN expression in Penl1 cells. Therefore, overexpression of ID1 could serve as a potential prognostic biomarker for the clinical management of PSCC. Strategies targeting ID1­regulated signaling pathways may have therapeutic benefit in PSCC.

Comparison of efficacy between brachytherapy and penectomy in patients with penile cancer: a meta-analysis.

We conducted a meta-analysis to compare the efficacy of brachytherapy and penectomy in patients with penile cancer. We searched the published articles in the PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang databases up to March 20, 2017. Twenty-two studies entered the final analyses. We used five-year overall survival rate, five-year local control rate, disease-free progression and lymph node positive rate to assess the efficacy. The meta-analysis found that patients who received penectomy had higher five-year local control rate (85% vs 80%, odds ratio = 0.72, 95% confidence interval: 0.58-0.90), five-year disease-free progression rate (77% vs 72%, odds ratio = 0.77, 95% confidence interval: 0.63-0.93) and lymph node positive rates (24% vs 20%, odds ratio = 0.79, 95% confidence interval: 0.64-0.98) than brachytherapy. No significant difference was observed for two group in five-year overall survival rate (76% vs 74%, odds ratios = 1.11 with the 95% confidence interval: 0.91-1.36). Both of penectomy and brachytherapy can improve the survival status. Penectomy provided better control efficacy, and not improved the survival status compared with brachytherapy solely. However, further research was required because of retrospective nature and potential bias of the data.

Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC.

Hepatocellular carcinoma (HCC) is a highly malignant tumor and can evolve rapidly to resistance to chemotherapies. Glycochenodeoxycholate (GCDA), which is toxic and hydrophobic, is the main ingredient in the bile and associated with carcinogenesis of gastrointenstinal tumors. Bcl-2 is the most important anti-apoptotic protein and overexpressed in various human tumors. In the present study, we found that GCDA can induce the chemoresistance of human liver cancer cells and specific depletion of Bcl-2 by RNA interference blocks GCDA-stimulated chemoresistance, which indicate the pivotal role of Bcl-2 in such process. Mechanistically, GCDA simultaneously stimulates phosphorylation of Bcl-2 at Ser70 site and activates extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of ERK1/2 by PD98059 (MAPK/ERK1/2 inhibitor) or siRNA (targeting ERK1/2) suppresses GCDA-stimulated phosphorylation of Bcl-2 and significantly attenuates the survival and chemoresistance induced by GCDA in liver cancer cells. Thus, GCDA-induced survival and chemoresistance of liver cancer cells may occur through activation of Bcl-2 by phosphorylation at Ser70 site through MAPK/ERK1/2 pathway, which may contribute to the development of human liver cancer and chemoresistance.

Increased expression of Cks1 protein is associated with lymph node metastasis and poor prognosis in nasopharyngeal carcinoma.

BACKGROUND: The Cks1 protein is an essential factor in regulating cell cycle by mediating the ubiquitination of CDK inhibitor p27kip1. It has been reported that aberrant expression of Cks1 and p27kip1 proteins was found in various tumors and related to initiation and progression of carcinomas. However, the potential roles which Cks1 and p27KIP1 proteins play in NPC remain unclear. This study aims to examine the expression status of Cks1 and p27kip1 and their possible prognostic significance in NPC. METHODS: Paraffin-embedded specimens with NPC (n = 168) and non-tumor nasopharyngeal tissues (n = 49) were analyzed by IHC. RESULTS: Expression of Cks1 increased in NPC tissues compared with non-tumor nasopharyngeal tissues (P < 0.05), whereas p27kip1 protein frequently expressed in non-tumor nasopharyngeal tissues compared with NPC tissues (P < 0.05). There was a significant reverse correlation between Cks1 and p27kip1 protein expression in NPC (r = -0.189, P < 0.05).In addition, Kaplan-Meier survival curve showed that there was a significant tendency of shorter overall survival (OS) in NPC patients with Cks1 positive expression compared to negative ones, especially in patients with lymph node metastasis (P < 0.001, respectively). But there was no significance between p27kip1 expression and survival viability of NPC patients. Multivariate Cox regression analysis further identified increased expression of Cks1 was the independent poor prognostic factor for NPC (p = 0.13). CONCLUSION: Our research found expression of Cks1 increased and was inverse to the expression of p27KIP1. High expression of Cks1 was significantly associated with lymph node metastasis and survival status in NPC. In addition, the abnormally high level of Cks1 protein was proved to be an independent poor prognostic factor in NPC. These results may provide novel clue for NPC therapy method.

Epithelial membrane protein 3 regulates TGF-ß signaling activation in CD44-high glioblastoma.

Although epithelial membrane protein 3 (EMP3) has been implicated as a candidate tumor suppressor gene for low grade glioma, its biological function in glioblastoma multiforme (GBM) still remains poorly understood. Herein, we showed that EMP3 was highly expressed in CD44-high primary GBMs. Depletion of EMP3 expression suppressed cell proliferation, impaired in vitro tumorigenic potential and induced apoptosis in CD44-high GBM cell lines. We also identified TGF-ß/Smad2/3 signaling pathway as a potential target of EMP3. EMP3 interacts with TGF-ß receptor type 2 (TGFBR2) upon TGF-ß stimulation in GBM cells. Consequently, the EMP3-TGFBR2 interaction regulates TGF-ß/Smad2/3 signaling activation and positively impacts on TGF-ß-stimulated gene expression and cell proliferation in vitro and in vivo. Highly correlated protein expression of EMP3 and TGF-ß/Smad2/3 signaling pathway components was also observed in GBM specimens, confirming the clinical relevancy of activated EMP3/TGF-ß/Smad2/3 signaling in GBM. In conclusion, our findings revealed that EMP3 might be a potential target for CD44-high GBMs and highlight the essential functions of EMP3 in TGF-ß/Smad2/3 signaling activation and tumor progression.

Increased NEK2 in hepatocellular carcinoma promotes cancer progression and drug resistance by promoting PP1/Akt and Wnt activation.

NIMA-related expressed kinase 2 (NEK2) participates in the carcinogenesis and progression of certain types of cancer, however, its expression and roles in the development of hepatocellular carcinoma (HCC) remains unknown. Here, we found that NEK2 expression was significantly upregulated in both human HCC tissues and cell lines, and increased NEK2 expression in HCC was significantly correlated with clinical progression of HCC in patients. Knockdown of NEK2 in HCC cells inhibited HCC progression, as determined by the suppressed cell proliferation, invasion and metastasis. Furthermore, knockdown of NEK2 inhibited drug resistance of HCC cells, as shown by the promoted suppression of cell viability in 5-fluorouracil (5­FU)­treated HCC cells. Mechanistically, protein phosphatase 1 (PP1)/Akt and Wnt signaling activation are significantly inhibited by NEK2 knockdown, which is responsible for the HCC progression and involved in NEK2­induced cancer cell abnormal biological behavior. Thus, enhanced NEK2 expression in HCC promotes HCC progression and drug resistance by promoting PP1/Akt and Wnt pathway activation, which may represent a new therapeutic target for HCC.

Loss of plexin-B3 in hepatocellular carcinoma.

Plexins are the primary receptors of semaphorins, and participate in the majority of intracellular pathways triggered by semaphorins, including the regulation of cell adhesion and the motility of numerous cell types. Recently, several studies have reported that plexins can significantly affect different aspects of cancer cell biology, and the aberrant expression of plexins has been observed in a wide variety of tumor types. However, the expression and role of plexin-B3 in hepatocellular carcinoma (HCC) is yet to be investigated. In the present study, plexin-B3 expression was measured in 14 paired HCC samples and the corresponding adjacent non-cancerous tissue by quantitative polymerase chain reaction and western blot analysis. The results indicated that the mRNA and protein expression levels of plexin-B3 were downregulated in HCC samples when compared with the corresponding adjacent non-cancerous tissue. In order to elucidate the correlation between clinicopathological data and the expression of plexin-B3 in patients with HCC, 84 HCC archived specimens were analyzed by immunohistochemistry (IHC). The IHC results revealed that the protein expression level of plexin-B3 was lower in the HCC samples compared with the corresponding adjacent non-cancerous tissue, and plexin-B3 underexpression was correlated with the patient gender and tumor size. In conclusion, these results indicated that loss of plexin-B3 in HCC may be of predictive value for the occurrence and progression of HCC. Thus, plexin-B3 may be a promising biomarker for the diagnosis and treatment of tumors in the future.

MicroRNA-145 inhibits cell proliferation by directly targeting ADAM17 in hepatocellular carcinoma.

MicroRNAs (miRNAs) are key regulators in cell processes. Emerging evidence has suggested that there is a direct association between miRNAs and cancer. However, the exact regulatory mechanisms of miRNAs in tumorigenesis are poorly understood. In the present study, we showed that miR-145 is able to significantly reduce mRNA and protein expression levels of A disintegrin and metalloproteinase 17 (ADAM17) in liver cancer cells (SMMC-7721, BEL-7402 and Huh-7). Dual luciferase reporter assays confirmed that ADAM17 is a direct target of miR-145. Notably, we found that miR-145 inhibits cell proliferation and growth activity in SMMC-7721 cells. These results demonstrated that it may be exert the function of tumor suppression in a particular link of cancer cell growth. Further studies revealed that the silencing of ADAM17 decreased the proliferation and growth activity of SMMC-7721 cells. Moreover, it reduced the expression of MMP-9. In conclusion, miR-145 inhibits liver cancer cell proliferation by directly targeting ADAM17. Thus, it may become a promising biological target in the treatment strategy of hepatocellular carcinoma.

Angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to psoriasis in a Chinese population.

INTRODUCTION: The relationship between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and psoriasis has previously been studied mainly in Caucasians and only once in Asians. The aim of this study is to evaluate the association between the ACE I/D polymorphism and the risk of psoriasis in a Chinese population. MATERIALS AND METHODS: The study population consisted of 668 psoriasis patients and 668 matched control subjects. The ACE I/D gene polymorphism was analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The frequency of the ACE II genotype (odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.06, 1.63; P = 0.01) and I allele (OR = 1.25, 95% CI = 1.06, 1.48; P = 0.01) in patients with psoriasis was significantly higher than that in the control group. And the D allele frequency in patients with psoriasis was significantly lower (OR = 0.80, 95% CI = 0.68, 0.95; P = 0.01) than that in the control group. When stratified by family history, the frequency of the DD genotype was marginally significantly lower in patients with a positive family history of psoriasis (familial psoriasis) than in those with negative (sporadic psoriasis) (OR = 0.47, 95% CI = 0.23, 0.97; P = 0.04). When stratified by onset of the disease, type of psoriasis and the severity of psoriasis, no statistically significant result was observed. CONCLUSION: Our study suggested that the ACE II genotype and I allele might confer susceptibility to psoriasis in a Chinese population.

[Effect of intermittent hypoxia on leptin and leptin receptor expression in obesity mice].

In order to explore the effect and underlying mechanism of hypoxia on body weight, the effect of intermittent moderate hypoxia on high-fat diet-induced obesity was observed in mice, and the role of leptin in hypoxic effect was identified. Healthy Kunming mice were divided randomly into 4 groups (n=20 in each group). The control group: the mice were fed normally under the normal oxygen pressure. Hypoxia group: the mice were fed normally, and given intermittent moderate hypoxia training. Obesity group: the mice were fed diet rich in fat and sugar under the normal oxygen pressure. Hypoxia + obesity group: the mice were fed diet rich in fat and sugar, and given intermittent moderate hypoxia training. After 40 d of feeding and training, the body weight of mice was determined, and the average increasing rate of body weight in each group was calculated and normalized with food intake. Meanwhile, plasma leptin level was measured with ELISA method, and fatty degeneration and leptin receptor expression in liver were observed by Sudan III staining and immunohistochemistry, respectively. The obesity mouse model was successfully established with increases in body weight, plasma leptin level and distribution of adipocytes in the liver. The average body weight and density of adipocytes in the liver in hypoxia and hypoxia + obesity groups decreased obviously, while plasma leptin level and leptin receptor expression in the liver were increased. It is suggested that intermittent moderate hypoxia reduces body weight through elevating plasma leptin level and/or enhancing leptin receptor expression in the liver.