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.

COPS3 Promotes Proliferation, Invasion, and EMT of Colorectal Cancer Cells by MEK/ERK Pathway.

Colorectal cancer (CRC) is one of the most aggressive cancers with poor prognosis and high mortality. The study of the pathogenesis of CRC is a top priority in providing effective diagnostic and prognostic strategies for CRC. COPS3 protein is a subunit of the COP9 signaling body (CSN), which is closely associated with the development of multiple types of tumors. However, there are few studies on the role of COPS3 in colon adenocarcinoma (COAD). This study investigated the effects of COPS3 on proliferation, motility, and EMT of colorectal cancer cells and related mechanisms. COPS3 was highly expressed in COAD. The depletion of COPS3 suppressed the viability and stimulated the apoptosis of COAD cells. Depletion of COPS3 suppressed the motility and EMT process of COAD cells. Mechanically, we found that COPS3 could mediate MEK/ERK pathway and therefore affected the process of COAD cells. We thought that COPS3 could serve as a promising COAD target.

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.

Biostudy on Traditional Chinese Medicine Massa Medicata Fermentata.

Massa Medicata Fermentata (MMF) has been used for a long time by the Chinese. MMF is used widely in feed additives and human medicinal applications throughout the world; however, there have only been a few reports about the biostudy of its fermentation mechanism and medicinal ingredients. To safely use MMF, we observed the changes in the ingredients and amylase activity for several raw materials during the fermentation process of MMF. We are going to explore the basis of pharmacodynamic substances and the purpose of MMF to provide support for safe use in clinics. This biostudy data demonstrated that the ingredients such as amygdalin, benzaldehyde, and rutin were gradually degraded during the process of fermentation, and the fermented MMF did not contain amygdalin and benzaldehyde. The HPLC fingerprint of fermented MMF for 7 days is similar to the chemical composition of the original unfermented MMF with a similarity of only 0.106. Meanwhile, the activities of amylase in fermented MMF had gradually increased, and the content of organic acids also had increased. According to our biostudy, we found that the raw material chemical composition of MMF in the process of fermentation was affected by microorganisms and various substances. The conclusions of our study determined that the initial components of MMF are not identical to the pharmacodynamic components. We also conclude that amylase activity explains the pharmacological activity of MMF to a certain extent, but it is likely not the only factor. The implication not only provides the initial knowledge of MMF but also implies the further exploration of this popular traditional medicine.

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.

Up-regulation of microRNA-302a inhibited the proliferation and invasion of colorectal cancer cells by regulation of the MAPK and PI3K/Akt signaling pathways.

Aberrant expression of microRNA-302a (miR-302a) has been frequently reported in some cancers excluding colorectal cancer (CRC). However, the role of miR-302a in CRC has not been reported. In this paper, we examined the effect of miR-302a overexpression on proliferation and invasion in CRC cells. The mRNA level of miR-302a in CRC cell lines was determined by real-time PCR. The miR-302a mimic was transiently transfected into CRC cells using Lipofectamine™ 2000 reagent. Subsequently, cell proliferation and invasion were assessed by MTT and Transwell assays. Western blot and ELISA assay were used to detect the expressions and secretions of matrix metalloproteinases (MMPs). Moreover, the expressions of epithelial marker, mesenchymal markers and transcription factors were also determined by Western blot. In addition, the effects of miR-302a overexpression on the MAPK and PI3K/Akt signaling pathways were investigated by Western blot. Our results showed that the mRNA level of miR-302a was remarkably decreased in CRC cell lines compared with normal colon epithelium cells. Up-regulation of miR-302a inhibited the proliferation and invasion of CRC cells. The expressions and secretions of MMP-9 and -2 were evidently reduced by increasing miR-302a. Besides, we found a decrease of ß-catenin, fibronection, vimentin, Snail, Slug, ZEB1 and ZEB2 expressions and an increase of E-cadherin expression. We also found that miR-302a overexpression might decrease the phosphorylation of Erk1/2 and Akt. Altogether, our results indicated that miR-302a overexpression was shown to inhibit proliferation and invasion of CRC cells by reducing the expressions of related proteins through suppressing the MAPK and PI3K/Akt signaling pathways.

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.

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.

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.