Kewei Jiang

Identification of transgelin-2 as a biomarker of colorectal cancer by laser capture microdissection and quantitative proteome analysis

To search for potential protein markers of colorectal cancer (CRC), the changes in protein expression levels between microdissected tumor cells and normal mucosa epithelia were analyzed by an acetylation stable isotopic labeling method coupled with linear quadrupole ion trap fourier transform mass spectrometry (LTQ‐FTMS). In total, 137 proteins were up‐regulated or down‐regulated significantly in cancer by at least two‐fold. Based on gene ontology analysis, the largest part of differential proteins were unknown for both subcellular localization and biological process. In particular, the significant up‐regulation of transgelin‐2 (TAGLN2) in CRC was validated by Western blot analysis and further evaluated by immunohistochemistry in paired tumor and normal mucosa samples from 120 consecutive CRC patients, 20 adenomas, and eight synchronous hepatic metastases of CRC. TAGLN2 expression was frequently observed in cancer cells, precancerous lesions, and hepatic metastases, whereas in normal epithelia expression was rarely observed. The overexpression of TAGLN2 was associated with lymph node and distant metastasis, advanced clinical stage (P < 0.001), and shorter overall survival in CRCs. Cox regression analysis indicated that high tumor‐TAGLN2 expression represents an independent prognostic factor. Consequently, over‐expression of TAGLN2 may serve as a new biomarker for predicting progression and prognosis of CRC. (Cancer Sci 2009)

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.

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.

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.

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.

Prospective controlled study of the safety and oncological outcomes of ELAPE procure with definitive anatomic landmarks versus conventional APE for lower rectal cancer

BACKGROUND The use of extra-levator abdominoperineal resection (ELAPE) procedure for lower rectal cancer is controversial. It is unclear whether the ELAPE procedure could improve surgical safety and lead to better oncological outcomes. METHODS Sixty-nine lower rectal cancer patients who underwent ELAPE (36 cases) or conventional abdominoperineal resection (APE; 33 cases) between June 2011 and February 2013 were prospectively investigated. Clinicopathological variables including blood loss, intraoperative perforation (IOP) rate, circumferential resection margin (CRM) involvement, lymph node harvest, the postoperative complications, urinary and sexual function, quality of life (QOL), local recurrence rate and survival were recorded and compared. RESULTS Blood loss (P = 0.021), perineal wound complication (P = 0.039), IOP rate (P = 0.028), local recurrence (P = 0.034) were significantly less frequent in the ELAPE group. There was greater CRM involvement in the conventional APE group but no statistical difference between the two groups. Urinary function, sexual function and QOL were not significantly different between the two groups. Overall survival and progression-free survival were not significantly different between two groups, even when survival was analyzed according to TNM stage, T stage, N stage, and with or without neoadjuvant chemoradiotherapy. In patients who underwent ELAPE there was no statistical difference in postoperative complications between younger and elderly patients (age ≥60). CONCLUSIONS ELAPE procedure with definitive anatomic landmarks demonstrated surgical safety and decreased local recurrence for lower rectal cancer patients including the elderly, but there were no survival improvements in compared to conventional APE procedure.

Downregulation of miR-199b is associated with distant metastasis in colorectal cancer via activation of SIRT1 and inhibition of CREB/KISS1 signaling

The progression of distant metastasis cascade is a multistep and complicated process, frequently leading to a poor prognosis in cancer patients. Recently, growing evidence has indicated that deregulation of microRNAs (miRNAs) contributes to tumorigenesis and tumor progression in colorectal cancer (CRC). In the present study, by comparing the miRNA expression profiles of CRC tissues and corresponding hepatic metastasis tissues, we established the downregulation of miR-199b in CRC metastasis tissues. The decrease in miR-199b expression was significantly correlated to late TNM stage and distant metastasis. Moreover, Kaplan–Meier curves showed that CRC patients with high expression level of miR-199b had a longer median survival. Functional assays results indicated that the restoration of miR-199b considerably reduced cell invasion and migration in vitro and in vivo, and increased the sensitivity to 5-FU and oxaliplatin. Further dual-luciferase reporter gene assays revealed that SIRT1 was the direct target of miR-199b in CRC. The expression of miR-199b was inversely correlated with SIRT1 in CRC specimens. SIRT1 knockdown produced effects on biological behavior that were similar to those of miR-199b overexpression. Furthermore, through Human Tumor Metastasis PCR Array we discovered KISS1 was one of the downstream targets of SIRT1. Silencing of SIRT1 upregulated KISS1 expression by enhancing the acetylation of the transcription factor CREB. The latter was further activated via binding to the promoter of KISS1 to induce transcription. Thus, we concluded that miR-199b regulates SIRT1/CREB/KISS1 signaling pathway and might serve as a prognosis marker or a novel therapeutic target for patients with CRC.

An anatomical, histopathological, and molecular biological function study of the fascias posterior to the interperitoneal colon and its associated mesocolon: their relevance to colonic surgery.

The study aim was to explore the anatomy, histopathology, and molecular biological function of the fascias posterior to the interperitoneal colon and its mesocolon to provide information for improving complete mesocolic excision. To accomplish this aim, we performed intraoperative observations in 60 interperitoneal colon‐cancer patients accepted for complete mesocolic excision and conducted local anatomy observations for five embalmed cadavers. An additional two embalmed child cadaver specimens were studied with large slices and paraffin sections. Ten of the 60 patients were examined with a lymph node tracer technique in vivo, while fresh specimens from these patients were assessed by histopathological examination and transwell cell migration assays in vitro. The anatomical and histopathological findings showed that the fascias posterior to the interperitoneal colon and its associated mesocolon were composed of two independent layers: the visceral and parietal fascias. These two fascias were primarily composed of collagen fibers, with the parietal fascia containing a small amount of muscle fiber. The in vivo test showed that the visceral fascia surrounded the colon and its associated mesocolon, including vessels and lymphatics, and that it had no lymphatic flow through it into the rear tissues. Moreover, the in vitro assays showed the visceral fascia was able to block tumor cell migration. Although many surgical scholars have known of the existence of fascia tissue posterior to the intraperitoneal colon, the detailed structure has been ignored and been unclear. As shown by our findings, the visceral and parietal fascias are truly formed structures that have not been previously reported. A thorough understanding of fascial structures and the function of the visceral fascia barrier in blocking tumor cells will facilitate surgeons when performing high‐quality complete mesocolic excision procedures.