NUSAP1 gene silencing inhibits cell proliferation, migration and invasion through inhibiting DNMT1 gene expression in human colorectal cancer.

Colorectal cancer (CRC) is one of the most common cause of cancer-related death in both female and male patients, with a high capacity for tumor migration and invasion. Recently, aberrant nucleolar and spindle-associated protein 1 (NUSAP1) expression has been reported in several cancers. However, the biological function and molecular mechanism of NUSAP1 in CRC have not been reported. Here, we demonstrated that NUSAP1 gene expression was notably upregulated in CRC tissues and cell lines (Caco2, LS174T, SW480, and LoVo). Subsequently, SW480 and LoVo cells were transfected with NUSAP1 siRNA, respectively, and the biological function of NUSAP1 was investigated. Results indicated that NUSAP1 silencing by siRNA inhibited CRC cell proliferation, and induces cell apoptosis. Moreover, NUSAP1 knockdown suppressed cell migration, cell invasion, and epithelial-to-mesenchymal transition (EMT). Furthermore, NUSAP1 silencing notably inhibited the mRNA and protein expression level of DNA methyltransferase 1 (DNMT1). DNMT1 overexpression partly rescued the effect of NUSAP1 silencing on colorectal cancer biological function. Taken together, NUSAP1 gene silencing induced cell apoptosis, and inhibited cell proliferation, cell migration, cell invasion, and EMT in colorectal cancer through inhibiting DNMT1 gene expression. These findings indicat that NUSAP1 is a promising molecular target for CRC treatment.

Effect of Proliferator-Activated Receptor-γ Pro12Ala Polymorphism on Colorectal Cancer Risk: A Meta-Analysis.

BACKGROUND: The association between peroxisome proliferators-activated receptor γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk is still controversial. A meta-analysis was performed. MATERIAL AND METHODS: We conducted a literature search using PubMed, EMBASE, and Cochran databases. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Fixed-effects and random-effects models were used. Dominant model, recessive model, and additive model were used in this meta-analysis. RESULTS: Fifteen studies including 13575 cases and 17085 controls were included in our meta-analysis. Result of this meta-analysis found that PPARγ Pro12Ala polymorphism was significantly associated with a reduced risk of CRC (OR=0.90; 95% CI 0.83-0.98; P=0.01). No significant association was found between PPARγ Pro12Ala polymorphism and CRC risk in Asians (OR=0.80; 95% CI 0.60-1.09; P=0.15). However, PPARγ Pro12Ala polymorphism was significantly associated with a reduced risk of CRC in Caucasians (OR=0.91; 95% CI 0.83-0.99; P=0.03). When stratified analysis was performed by CRC site, no positive association was found between PPARγ Pro12Ala polymorphism and rectal cancer (OR=0.95; 95% CI 0.74-1.22; P=0.71). However, a reduced risk of colon cancer was observed (OR=0.85; 95% CI 0.76-0.94; P=0.002). CONCLUSIONS: In summary, this study suggests that PPARγ Pro12Ala polymorphism was a protective factor of CRC.

Inhibition of secretory leukocyte protease inhibitor (SLPI) promotes the PUMA-mediated apoptosis and chemosensitivity to cisplatin in colorectal cancer cells.

BACKGROUND: Aberrant expression of Secretory Leukocyte Protease Inhibitor (SLPI) has been associated with human cancer growth and its suppression was identified as a potential target for anti-cancer drugs, particularly in colorectal cancer. However, the underlying mechanism by which SLPI affected the development of drug resistance in CRC remains unclear. OBJECTIVE: This study investigated the role of SLPI in the p53-up-regulated modulator of apoptosis (PUMA)-mediated CRC cells' apoptosis and their chemosensitivity to Cisplatin. METHODS: A series of qRT-PCR and western blot analyses were performed to characterize the expressions of SLPI, PUMA, and Akt in CRC lines. Tunel, transwell, and CCK-8 analyses were monitored to define the impacts of the siRNA-mediated knockdown of SLPI on CRC cell development. Furthermore, in vivo development of CRC was evaluated in nude mice infected with siSLPI or Cisplatin alone or both, and Ki67 and caspase-3 immunohistochemistry assay was monitored on multiple tissue microarray from the same cohort. RESULTS: Our results showed that SLPI inhibition strongly promoted the expressions of the pro-apoptotic protein PUMA, cleaved-caspase3 and Bax and reduced the cell viability of HT29 and HT116 cell lines in vitro. In addition, siSLPI knockdown effectively suppressed both Akt and FoxO3 proteins and improved the sensitivity to cisplatin chemotherapy. Xenograft tumor assay revealed a lowered growth in mice treated with Cisplatin, while combined treatment of siSLPI achieved more significant anticancer effects than Cisplatin alone. CONCLUSIONS: Taken together, these findings demonstrated that suppression of SLPI might repress the growth of human colorectal cancer cells both in vitro and in vivo. These results suggested SLPI as a novel resistance factor to Cisplatin, and a combination of Cisplatin and SLPI inhibitor be beneficial for colorectal cancer therapy.

Targeting secretory leukocyte protease inhibitor (SLPI) inhibits colorectal cancer cell growth, migration and invasion via downregulation of AKT.

The secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor which plays important role in bacterial infection, inflammation, wound healing and epithelial proliferation. Dysregulation of SLPI has been reported in a variety of human cancers including glioblastoma, lung, breast, ovarian and colorectal carcinomas and is associated with tumor aggressiveness and metastatic potential. However, the pathogenic role of SLPI in colorectal cancer is still unclear. Here we showed that SLPI mRNA level was significantly upregulated in colorectal cancer tissues compared to adjacent normal controls. Targeting SLPI by siRNA inhibited proliferation, migration and invasion of colorectal cancer cells lines HT29 and HT116 in vitro. Mechanistically, blockage of cancer cell growth and metastasis after SLPI knockdown was associated with down-regulation of AKT signaling. In conclusion, SLPI regulated colorectal cell growth and metastasis via AKT signaling. SLPI may be a novel biomarker and therapeutic target for colorectal cancer. Targeting AKT signaling may be effective for colorectal cancer treatment.

MiR-208a enhances cell proliferation and invasion of gastric cancer by targeting SFRP1 and negatively regulating MEG3.

The present studies have identified that microRNAs function as regulators in different diseases including cancers. However, the expression patterns and underlying molecular mechanisms of miR-208a involved in gastric cancer (GC) remain little known. In the study, our results demonstrated that miR-208a expression was significantly increased in GC tissues compared with adjacent normal tissues by performing qRT-PCR. Higher miR-208a expression was association with lymph node metastasis and TNM stage in GC patients. Kaplan-Meier analysis verified that patients with higher miR-208a expression were significantly associated with shorter overall survival (OS) time. Univariate and multivariate Cox analysis revealed that lymph node metastasis, TNM stage and higher miR-208a were independent risks factors of OS time. Ectopic expression of miR-208a by treatment with miR-208a mimic promoted cell proliferation and invasion abilities, but downregulation of miR-208a by treatment with miR-208a inhibitor had an opposite effects. Furthermore, we identified specific targeting sites for miR-208a in the 3'-untranslated region (3'-UTR) of the SFRP1 gene by dual-luciferase reporter assay. Upregulation of MiR-208a promoted cell proliferation and invasion by suppressing SFRP1 expression in GC cells. Moreover, dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and qRT-PCR analysis demonstrated that miR-208a targeted MEG3 and negatively regulated MEG3 expression in GC cells. Thus, these data indicated that miR-208a promoted GC progression by targeting SFRP1 and negatively regulating MEG3, which may be a potential therapeutic target of GC.

Meta-analysis in the association between obesity and risk of thyroid cancer.

Although many epidemiologic studies have investigated obesity and thyroid cancer risk, definite conclusions cannot be drawn. To clarify the effects of obesity on the risk of thyroid cancer, a meta-analysis was performed. Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) till 16 Aug 2014. Pooled RRs and 95% CIs were used to assess the strength of the associations. A total of 16 studies including 12616154 subjects were involved in this meta-analysis. A significantly elevated thyroid cancer risk was found in overall analysis (RR = 1.29, 95% CI 1.20-1.37, P < 0.00001). In the gender subgroup analyses, a statistically significant association was found in male patients (RR = 1.35, 95% CI 1.16-1.58, P = 0.0001) and in female patients (RR = 1.29, 95% CI 1.19-1.40, P < 0.00001). When we limited the meta-analysis to studies that controlled for age (RR = 1.34, 95% CI 1.24-1.44, P < 0.00001), smoke (RR = 1.36, 95% CI 1.22-1.52, P < 0.00001), alcohol use (RR = 1.40, 95% CI 1.15-1.71, P = 0.0009), and history of benign thyroid disease (RR = 1.51, 95% CI 1.24-1.83, P < 0.0001), a significant association between obesity and thyroid cancer risk remained. This meta-analysis provides the evidence that obesity may contribute to the thyroid cancer development.

Association between matrix metalloproteinase 1 -1607 1G>2G polymorphism and cancer risk: a meta-analysis including 19706 subjects.

The association between MMP1 -1607 1G>2G polymorphism and cancer risk has been reported, but results remained controversial and ambiguous. To assess the association between MMP1 -1607 1G>2G polymorphism and cancer risk, a meta-analysis was performed. Based on comprehensive searches of the PubMed, Elsevier Science Direct, Excerpta Medica Database (Embase), and Chinese Biomedical Literature Database (CBM), we identified outcome data from all articles estimating the association between MMP1 -1607 1G>2G polymorphism and cancer risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Thirty-eight studies involving 10178 cases and 9528 controls were included. Overall, significant association between MMP1 -1607 1G>2G polymorphism and cancer susceptibility was observed for additive model (OR = 1.21, 95% CI 1.09-1.35), for codominant model (OR = 1.34, 95% CI 1.10-1.63), for dominant model (OR = 1.17, 95% CI 1.01-1.34), for recessive model (OR = 1.31, 95% CI 1.14-1.52). In the subgroup analysis by ethnicity, the significant association was found among Asians but not among Caucasians. In the subgroup analysis by site of cancer, significant associations were found among lung cancer, colorectal cancer, head and neck cancer and bladder cancer. This meta-analysis demonstrated that the MMP1 -1607 1G>2G polymorphism was significantly associated with cancer risk.

Effect of neoadjuvant chemotherapy combined with hyperthermic intraperitoneal perfusion chemotherapy on advanced gastric cancer.

Neoadjuvant and hyperthermic intraperitoneal chemotherapies have been shown to be effective in the treatment of resectable advanced gastric cancer. The aim of the present study was to investigate the clinical efficiency and security of neoadjuvant chemotherapy in combination with hyperthermic intraperitoneal chemotherapy for the treatment of postoperative advanced gastric cancer. A total of 192 patients diagnosed with advanced gastric cancer were randomly divided into the following four groups (n=48 per group): Control, neoadjuvant chemotherapy, hyperthermic intraperitoneal perfusion chemotherapy and joint groups. The joint group received neoadjuvant chemotherapy combined with hyperthermic intraperitoneal perfusion chemotherapy. Complications, adverse reactions, recurrence rates within 2 years and the 1- and 3-year survival rates following surgery were observed. No significant differences were observed in the occurrence rates of I-II degree myelosuppression, III-IV degree myelosuppression, I-II degree nausea or III-IV degree nausea and vomiting among the four groups (P>0.05). The median progression-free survival times were 26, 31, 33 and 28 months in the control, neoadjuvant chemotherapy, hyperthermic intraperitoneal perfusion chemotherapy and joint groups, respectively (P<0.001). Compared with the control group, the recurrence-free 2-year survival rate of the joint group was significantly lower (P=0.04). The difference among the median survival times of the four groups was statistically significant (P=0.001). The 1-year survival rate of the joint group was significantly higher when compared with the control group and the difference was statistically significant (P=0.03). However, no statistically significant difference was identified among the 1-year survival rates of the four groups (P>0.05). Compared with the control group, the 3-year survival rates of the other three groups were significantly higher (P<0.05). Therefore, the results of the present study indicated that neoadjuvant chemotherapy combined with hyperthermic intraperitoneal perfusion chemotherapy for the treatment of advanced gastric cancer is well tolerated and exhibits improved compliance and efficiency.