Zhanlong Shen

Metabolic syndrome is an important factor for the evolution of prognosis of colorectal cancer: survival, recurrence, and liver metastasis.

BACKGROUND Several studies have shown that metabolic syndrome (MS) was a risk factor for colorectal cancer, but few studies have reported the relationship between MS and the prognosis of colorectal cancer. METHODS Data were collected from 507 cases of colorectal carcinoma between January 2002 and March 2007 to establish the database. These patients were divided into 2 groups based on the presence of MS. We tested the prognostic value of MS in the patients. The risk of adverse events was examined by Cox proportional hazard modeling. RESULTS The rates of liver metastasis and tumor recurrence were higher in the group of patients with colorectal cancer accompanied by MS. Moreover, MS is one of the important elements that independently can influence the survival (colonic carcinoma: hazard ratio [HR], 1.633; 95% confidence interval [CI], 1.039-2.565; rectal carcinoma: HR, 1.939, 95% CI, 1.076-3.494) and liver metastasis (colonic carcinoma: HR, 2.619; 95% CI, 1.288-5.324; rectal carcinoma: HR, 2.814; 95% CI, .962-2.888) of both colonic and rectal carcinoma patients, and MS patients have the highest risk with worse survival and liver metastases compared with other parameters. CONCLUSIONS The results suggest that MS may be an important prognostic factor for colorectal cancer, decreasing the incidence of MS may improve the therapeutic efficacy of colorectal cancer.

MiR-194, commonly repressed in colorectal cancer, suppresses tumor growth by regulating the MAP4K4/c-Jun/MDM2 signaling pathway

Tumor growth cascade is a complicated and multistep process with numerous obstacles. Until recently, evidences have shown the involvement of microRNAs (miRNAs) in tumorigenesis and tumor progression of various cancers, including colorectal cancer (CRC). In this study, we explored the role of miR-194 and its downstream pathway in CRC. We acquired data through miRNA microarray profiles, showing that the expression of miR-194 was significantly suppressed in CRC tissues compared with corresponding noncancerous tissues. Decreased miR-194 expression was obviously associated with tumor size and tumor differentiation, as well as TNM stage. Both Kaplan–Meier and multivariate survival analysis showed that downregulated miR-194 was associated with overall survival. Moreover, functional assays indicated that overexpression of miR-194 in CRC cell lines inhibited cell proliferation both in vitro and in vivo. In addition, using dual-luciferase reporter gene assay, we found MAP4K4 was the direct target of miR-194. Silencing of MAP4K4 resulted in similar biological behavior changes to that of overexpression of miR-194. We also observed through Human Gene Expression Array that MDM2 was one of the downstream targets of MAP4K4. Knockdown of MAP4K4 downregulated MDM2 expression through transcription factor c-Jun binding to the −1063 to -1057 bp of the promoter. These results suggest that miR-194, regulating the MAP4K4/c-Jun/MDM2 signaling pathway, might act as a tumor suppressor and serve as a novel target for CRC prevention and therapy.

Kindlin-2: a novel adhesion protein related to tumor invasion, lymph node metastasis, and patient outcome in gastric cancer

BACKGROUND Kindlin-2 has been confirmed as an essential element of bidirectional integrin signaling. In recent years, the relationship between Kindlin-2 expression and cancers has been a focus of interest. However, the relationship between Kindlin-2 expression in gastric cancer and tumor invasion, metastasis, and the outcome of patients have not been studied. METHODS Kindlin-2 expression at protein and RNA levels were detected by Western blot and real-time polymerase chain reaction in 40 pairs of gastric cancer samples. In addition, the correlations between Kindlin-2 expression and clinicopathologic factors as well as the prognosis of the patients were analyzed. Multivariate Cox regression was used to study the effect of Kindlin-2 expression on overall and progression-free survival. RESULTS We found that Kindlin-2 was up-regulated both at RNA (P = .027) and protein levels (P = .014) in gastric cancer tissues. Tumor samples with high Kindlin-2 expression (Kindlin-2/β-actin:tumor tissue/paraneoplastic tissue, ≥2) was observed in 55% of the patients. Moreover, Kindlin-2 expression had a significant positive correlation with tumor stromal invasion (P = .014), lymph node metastasis (P = .007), and TNM stage (P = .014). Patients with high Kindlin-2 expression had significantly poorer overall survival (P = .012) and progression-free survival (P = .012). High Kindlin-2 expression was an independent risk factor of progression-free survival (hazard ratio, 5.2; 95% confidence interval, 1.1-3.3; P = .032). CONCLUSIONS Kindlin-2 may play an important role in the development of gastric cancer and it is a potential factor that could be used to evaluate the outcome of gastric cancer. Kindlin-2 may shed new light on evaluating the prognosis and targeted therapy of gastric cancer.

A novel molecular marker for early detection and evaluating prognosis of gastric cancer: N-myc downstream regulated gene-1 (NDRG1)

Abstract Objective. N-myc downstream regulated gene-1 (NDRG1) is known as a differentiation-related gene that plays important roles in cell differentiation, organ formation, and embryonic development. NDRG1 was recently found to significantly down regulate in a variety of different neoplasms. Its significance in gastric cancer has not been studied. Materials and methods. NDRG1 was detected at its protein level by immunohistochemistry in formalin-fixed and paraffin-embedded sections with a total of 110 pair gastric cancer specimens including tumor and corresponding paraneoplastic tissues; NDRG1 mRNA was detected by real time-polymerase chain reaction. Meanwhile, the correlations between NDRG1 and clinicopathological factors were observed. Overexpression of NDRG1 has influence on the biological behavior of gastric cancer cell, which was detected by cell growth assay, apoptosis assay, and in vitro motility and invasion assay. Results. NDRG1 protein was down regulated in gastric cancer tissues, and the NDRG1 low expression rate was 73.6% (79/110). Moreover, NDRG1 expression has a significant inverse correlation with tumor stromal invasion, lymph node metastasis, pathological stage, but not with distant metastasis. The patients with low NDRG1 expression had a significantly shorter survival opportunity than those with high NDRG1 expression. In addition, overexpression of NDRG1 induced early apoptosis and inhibited SGC7901 cell proliferation and its motility and invasion capability. Conclusions. NDRG1 plays a significant role in carcinogenesis and preventing the metastasis and invasion of gastric cancer cells. NDRG1 could be developed as a marker contributing to diagnosis and evaluating prognosis in gastric cancer, as well as a potential therapeutic target of gastric cancer.

MicroRNA-217 functions as a prognosis predictor and inhibits colorectal cancer cell proliferation and invasion via an AEG-1 dependent mechanism.

BackgroundRecent studies have indicated the possible function of miR-217 in tumorigenesis. However, the roles of miR-217 in colorectal cancer (CRC) are still largely unknown.MethodsWe examined the expression of miR-217 and AEG-1 in 50 CRC tissues and the corresponding noncancerous tissues by qRT-PCR. The clinical significance of miR-217 was analyzed. CRC cell lines with miR-217 upregulation and AEG-1 silencing were established and the effects on tumor growth in vitro and in vivo were assessed. Dual-luciferase reporter gene assays were also performed to investigate the interaction between miR-217 and AEG-1.ResultsOur data demonstrated that miR-217 was significantly downregulated in 50 pairs of colorectal cancer tissues. MiR-217 expression levels were closely correlated with tumor differentiation. Moreover, decreased miR-217 expression was also associated with shorter overall survival of CRC patients. MiR-217 overexpression significantly inhibited proliferation, colony formation and invasiveness of CRC cells by promoting apoptosis and G0/G1 phase arrest. Interestingly, ectopic miR-217 expression decreased AEG-1 expression and repressed luciferase reporter activity associated with the AEG-1 3′-untranslated region (UTR). AEG-1 silencing resulted in similar biological behavior changes to those associated with miR-217 overexpression. Finally, in a nude mouse xenografted tumor model, miR-217 overexpression significantly suppressed CRC cell growth.ConclusionsOur findings suggest that miR-217 has considerable value as a prognostic marker and potential therapeutic target in CRC.

IL10, IL11, IL18 are differently expressed in CD14+ TAMs and play different role in regulating the invasion of gastric cancer cells under hypoxia.

BACKGROUND Recent evidence shows that chronic inflammation mediated by tumor-associated macrophage (TAM) play an important role in malignant tumor formation and progression. Interleukins expressed in TAMs regulate this progress. Hypoxia is a salient feature of solid tumors and has a profound influence on the biology of TAMs However, the role of interleukins in the gastric cancer progression under hypoxia is not clear. METHODS Realtime RT-PCR was used to quantitatively investigate the IL10, IL11 and IL18 expression in CD14(-) normal macrophages and CD14(+) TAMs co-cultured with four gastric cancer cell lines including non-metastatic cell line AGS and metastatic cell lines HGC-27, Hs-746T and NCI-N87 under normal or hypoxic conditions. In addition, the correlation between IL10, IL11, IL18 expression in TAMs under hypoxia and mobility of gastric cancer cells were analyzed. RESULTS Under normal conditions, the IL10 and IL18 expressions were significantly higher in CD14(+) TAMs co-cultured with non-metastatic cell line than with metastatic cell lines. IL11 expression was significantly higher in CD14(+) TAMs co-cultured with distant metastasis cell lines. Hypoxia induced IL10, IL11 and IL18 expression up regulated significantly in TAMs co-cultured with AGS, Hs-746T and NCI-N87 cell line. There was a significant negative correlation between IL11 expression in CD14(+) TAMs and gastric cancer cell invasion speed under hypoxic conditions (r=0.861, P<0.001). CONCLUSION The up-regulation of IL10, IL11 and IL18 expression in TAMs by hypoxia differed in gastric cancer cell lines. IL11 expression in TAMs might play more important role than IL10 and IL18 expression in regulating the invasion of gastric cancer cells under hypoxia.

Novel focal adhesion protein kindlin-2 promotes the invasion of gastric cancer cells through phosphorylation of integrin β1 and β3

We have found that the expression of the novel focal adhesion protein kindlin‐2 had a significant positive correlation with poor survival in gastric cancer. However, the mechanism by which kindlin‐2 acts in gastric cancer warrants further evaluation.

Clinical study on the correlation between metabolic syndrome and colorectal carcinoma.

Background:  Although metabolic syndrome (MS) has received a lot of attention in recent years, the correlation between MS and colorectal carcinoma is still not very clear. This study aims at exploring the relationship between MS and colorectal carcinoma.

Both macrophages and hypoxia play critical role in regulating invasion of gastric cancer in vitro

Abstract Background. As previously demonstrated, tumor associated macrophages (TAMs) infiltration is associated with some cancers invasion and metastasis. However, the role of TAMs in the gastric cancer remains unclear. Methods Three- dimensional dynamic migration imaging system and real time RT-PCR were used to quantitatively investigate the effect of macrophages on the cancer cell mobility and gene expression related to cancer invasion and metastasis, including ADAM8, ADAM9, MMP9, TIMP3, VEGF-A and IL8 genes, in AGS, HGC-27, Hs-746T and NCI-N87 gastric cancer cell lines under normal or hypoxic conditions. Results. Under normal conditions, the cancer cell invasion rate was increased significantly and all six gene expressions were upregulated in all four cancer cell lines by macrophages. Under hypoxia the changes in the cancer cell invasion rate induced by macrophages was negatively correlated to the TIMP3 expression. In non- metastatic cell line AGS, the increase in migration rate induced by macrophages was further elevated under hypoxia with increased ADAM8 and ADAM9 expression and decreased MMP9 and TIMP3 expressions. Under hypoxia, the induction by macrophages for IL-8 expression was increased significantly in distant metastatic cell lines NCI-N87 and HS-746T, VEGF-A was increased in HGC-27 cell line. Conclusions. Both macrophages and hypoxia play an indispensable role in regulating the invasion of gastric cancer cells in vitro; ADAMs, MMP9 and TIMP3 might be involved in TAM induced invasive power of gastric cancer cells.

Carcinosarcoma of pancreas with liver metastasis combined with gastrointestinal stromal tumour of the stomach: is there a good prognosis with the complete resection?

We report a carcinosarcoma of the pancreas with liver metastasis combined with gastrointestinal stromal tumour (GIST) of the stomach in a 72-year-old woman who presented with right upper quadrant pain, nausea and vomiting. A radical resection including pancreaticoduodenectomy, left hepatic lobe resection and local resection of the gastric mass was performed. The tumour in the head of pancreas was found to be grossly yellow-white, and it infiltrated the common bile duct and duodenum; the mass of the liver metastasis is solitary. Pathologic examination showed two components separated from each other: one component was a conventional infiltrating pancreatic ductal adenocarcinoma, and the other component showed sarcomatous growth pattern composed of pleomorphic spindle cells. The neoplasm of the stomach was confirmed a low malignant potential GIST by histology and immunohistochemistry. The patient was obliged to be in hospital because of abnormal bowel function; moreover, surveillance CT scans performed at 1.5 months post-operatively showed multiple liver metastasis and recurrence in the tail of pancreas. Unfortunately, the patient died of multiple organ failure at 2 months post-operatively. To our knowledge, this is the first experience report about surgical treatment of carcinosarcoma of pancreas with liver metastasis combined with GIST of the stomach. The patient performed a radical surgery for the metastatic carcinosarcoma even if that could be resected completely did not have a good consequence.