Expression of NOS and HIF-1αin human colorectal carcinoma and implication in tumor angiogenesis

AIM: To study CD34, CD105, inducible nitric oxide synthase (iNOS), endogenous nitric oxide synthase (eNOS), and hypoxia-inducible factor 1 (HIF-1)αexpression in human colorectal carcinomas. METHODS: The tissue microarrays (TMAs) were made up of 80 cases of colorectal carcinoma and 80 cases of non-neoplasm colorectal mucosa. The expression of CD34, CD105, NOS and HIF-1αwas detected by immunohistochemistry (S-P). RESULTS: iNOS and HIF-1αexpression in colorectal carcinoma was significantly higher than in non-neoplasm colorectal mucosa (X2 = 43.166, P < 0.01; X2 = 10.4278, P < 0.01); eNOS expression in colorectal carcinoma was significantly lower than in non-neoplasm colorectal mucosa (X2 = 11.354, P < 0.01). The expression of iNOS correlated with differentiation (X2 = 18.141, P < 0.01), invasive depth (X2 = 4.748, P < 0.01), and Micro vessel density (MVD) (t = 2.327, P < 0.05). The expression of HIF-1αwas correlated with infiltrating depth (X2 = 4.397, P < 0.05), Duke's staging (X2= 4.255, P < 0.05), and MVD (t = 2.272, P < 0.05). No correlation was found in eNOS expression. CONCLUSION: Over-expression of iNOS and HIF-1αin colorectal carcinoma is correlated with the biological character MVD.     

Serum IL-6, TNFα and CRP levels in Greek colorectal cancer patients: Prognostic implications

AIM: The significance of preoperative serum IL-6, TNFα and CRP levels in the progression of colorectal cancer (CRC) has not been fully elucidated. Our intention was to investigate their role and identify their prognostic significance. METHODS: The IL-6, TNFa and CRP levels were measured in 74 CRC patients and the relationships between their elevations and both the clinicopathological factors and prognosis of patients were investigated. Serum concentrations of human IL-6 and TNFα were determined by enzyme-linked immunosorbent assay (ELISA). CRP was measured by an immunoturbinometric method. RESULTS: Median IL-6, TNFα and CRP levels were significantly higher in CRC patients than in normal controls. High levels of serum IL-6, TNFα and CRP were correlated with larger tumor size. Furthermore, high IL-6 and high CRP levels were associated with reduced overall survival. CONCLUSION: Serum IL-6, TNFα and CRP levels definitely increase in CRC patients. Pre-operative serum elevation of IL-6 and CRP was thus found to be predictor of the prognosis of CRC patients. The clinical value of TNFα in CRC needs to be further investigated.     

Expression and significance of HIF-1α and VEGF in rats with diabetic retinopathy

Objective:To investigate the expression of hypoxia inducible iaclor-1α(HIF-1α)and vascular endothelial growth factor(VECF)in diabelic retinopathy(DR)rats and its effect on the DR occurrence and development.Methods:A total of 120 SD rats were randomly divided into trial group and control group with 60 in each.STZ.i.p.was used in the trial group to establish the DM model,citrate buffer salt of same amount was used up.to the control group.1,3 and 6 months after injection,respective 20 rats were sacrificed in each group to observe expression of HIF-1αand VEGF in the rat retina tissue at different lime points.Results:Expression of HIF-1αand VEGF were negative in the control group;expression of HIF-1αand VKGF protein in retinal tissue were weak after 1 month of DR mold formation.It showed progressive enhancement along with the progression in different organizations,differences between groups were significant(P0.05).Conclusions:Expressions of HIF-1αand VF.GF were;correlated with disease progression in early diabelic relinopathy.Retinal oxygen can induce over-expression of HIF-1αand VEGF.It shows that HIF-1αand VEGF play an important role in the pathogenesis of DR.     

Semaphorin 4D and hypoxia-inducible factor-1α overexpression is related to prognosis in colorectal carcinoma

AIM:To investigate semaphorin 4D(Sema4D)and hypoxia-inducible factor-1α(HIF-1α)expression in colorectal carcinoma and evaluate their clinicopathological and prognostic significance.METHODS:Eighty-six curatively resected colorectal carcinoma patients at different stages of disease were randomly selected from the group of patients who underwent surgery,and none of them received preoperative radiochemotherapy.Normal proximal adjacent bowel tissue,which served as an internal control,was obtained from 52 randomly selected patients.Immunohistochemistry was performed to analyze the expression of Sema4D and the tumor angiogenesisrelated protein HIF-1αin normal colorectal tissues and colorectal carcinoma tissues.The relationships between the expression and clinical characters and prognosis were analyzed.RESULTS:HIF-1αand Sema4D were positively expressed in 58%and 60%of colorectal carcinoma tissues,respectively.Significantly lower expression levels were observed in normal mucosa(8%and 12%,respectively).HIF-1αand Sema4D expression was closely correlated with histological tumor type,tumornode-metastasis(TNM)stage,and lymphatic metastasis(P0.05),but not with age or tumor size(P0.05).HIF-1αand Sema4D protein expression was significantly correlated with prognosis of colorectal carcinoma,as determined by Spearman rank correlation analysis(r=0.567;P0.01).Multivariate Cox analysis revealed that only Sema4D expression played a significant role in predicting patient prognosis(P0.05).CONCLUSION:These findings suggest that HIF-1αand Sema4D expression correlates with histological tumor type,TNM stage,and lymphatic metastasis in colorectal carcinoma and that Sema4D is a prognostic indicator of colorectal carcinoma.     

Expression of NOS and HIF-1α in human colorectal carcinoma and implication in tumor angiogenesis

AIM: To study CD34, CD105, inducible nitric oxide synthase (iNOS), endogenous nitric oxide synthase (eNOS), and hypoxia-inducible factor 1 (HIF-1) alpha expression in human colorectal carcinomas. METHODS: The tissue microarrays (TMAs) were made up of 80 cases of colorectal carcinoma and 80 cases of non-neoplasm colorectal mucosa. The expression of CD34, CD105, NOS and HIF-1alpha was detected by immunohistochemistry (S-P). RESULTS: iNOS and HIF-1alpha expression in colorectal carcinoma was significantly higher than in non-neoplasm colorectal mucosa (c2 = 43.166, P < 0.01; c2 = 10.4278, P < 0.01); eNOS expression in colorectal carcinoma was significantly lower than in non-neoplasm colorectal mucosa (c2 = 11.354, P < 0.01). The expression of iNOS correlated with differentiation (c2 = 18.141, P < 0.01), invasive depth (c2 = 4.748, P < 0.01), and Micro vessel density (MVD) (t = 2.327, P < 0.05). The expression of HIF-1alpha was correlated with infiltrating depth (c2 = 4.397, P < 0.05), Dukeos staging (c2 = 4.255, P < 0.05), and MVD (t = 2.272, P < 0.05). No correlation was found in eNOS expression. CONCLUSION: Over-expression of iNOS and HIF-1alpha in colorectal carcinoma is correlated with the biological character MVD.     

Meta-analysis of immunohistochemical expression of hypoxia inducible factor-1α as a prognostic role in gastric cancer

AIM:To conduct a meta-analysis to evaluate the prognostic role of hypoxia inducible factor-1α(HIF-1α)expression in gastric cancer.METHODS:The PubMed,EMBASE,and Web of Science databases were searched systematically for all articles published in English before August,2013.Pooled effect was calculated from the available data to evaluate the association between HIF-1αexpression and 5-year overall survival and tumor clinicopathological features in gastric cancer patients.Pooled odds ratios(ORs)with95%CIs were calculated using either a fixed-effects or a random-effects model.RESULTS:Nine studies matched the selection criteria,which reported on 1103 subjects,548 of whom had HIF-1αpositive expression(50%).This meta-analysis indicated that HIF-1αpositive expression in gastric cancer correlated with lower 5-year overall survival(OR=0.36;95%CI:0.21-0.64),worse tumor differentiation(OR=0.38;95%CI:0.23-0.64),deeper invasion(OR=0.42;95%CI:0.32-0.57),higher rates of lymph node metastasis(OR=2.23;95%CI:1.46-3.40),lymphatic invasion(OR=2.50;95%CI:1.46-4.28),and vascular invasion(OR=1.80;95%CI:1.29-2.51),and higher TNM stage(Ⅲ+Ⅳ)(OR=0.31;95%CI:0.15-0.60).CONCLUSION:HIF-1αpositive expression indicates a poor prognosis for patients with gastric cancer.Further studies are required to confirm these results.     

Up-regulation of hnRNP A1, Ezrin, tubulin ��-2C and Annexin A1 in sentinel lymph nodes of colorectal cancer

AIM: To investigate the early metastasis-associated proteins in sentinel lymph node micrometastasis (SLNMM) of colorectal cancer (CRC) through comparative proteome. METHODS: Hydrophobic protein samples were extracted from individual-matched normal lymph nodes (NLN) and SLNMM of CRC. Differentially expressed protein spots were detected by two-dimensional electrophoresis and image analysis, and subsequently identified by matrix assisted laser desorption/ionization-time of flight mass spectrometry-mass spectro...     

Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma

AIM: To investigate the expression of CD73 and hypoxia-inducible factor-1α (HIF-1α) in human gastric carcinoma, and explore their clinical significance and prognostic value. METHODS: CD73 and HIF-1α expressions were detected by immunohistochemistry in consecutive sections of tissue samples from 68 gastric carcinoma patients. The peritumor tissues 2 cm away from the tumor were obtained and served as controls. The presence of CD73 and HIF-1α was analyzed by immunohis-tochemistry using the Envision technique. RESULTS: CD73 and HIF-1α expressions in gastric carcinoma were significantly higher than those in gastric mucosal tissues as control (P < 0.001) and showed a close correlation (Spearman r = 0.390, P = 0.001). Overexpression of CD73 was positively correlated with differentiation of tumor (P = 0.000), histopathology (P = 0.041), depth of invasion (P < 0.001), nodal status (P = 0.003), metastasis (P = 0.013), and the American Joint Committee on Cancer (AJCC) stage (P < 0.001). High expression of HIF-1α was positively correlated with tumor diameter (P = 0.031), depth of invasion (P = 0.022), and AJCC stage (P = 0.035). The overall survival rate was low in the patients with high expression of CD73 (P < 0.001). Moreover, CD73+/HIF-1α+ patients had the worst prognosis (P < 0.001). CD73 expression was proven to be an independent predictor for patients with gastric carcinoma by both multivariate Cox regression analysis (P = 0.021) and receiver operating characteristic curves (P = 0.001).CONCLUSION: CD73 expression correlates closely with HIF-1α expression in gastric carcinoma. CD73 could be an independent prognostic indicator for gastric carcinoma.     

Expression of hypoxia-inducible factor 1α in gastric cancer and its clinical signficance

<正>Objective To explore the expression level and location of hypoxia-inducible factor 1α(HIF1α)in gastric cancer(GC)tissues and their relationship with clinicopathological features and clinical outcomes.Methods From July to September 2015,27 pairs of fresh paired GC tissues and adjacent normal tissues were gathered from the Eighth Department of General Surgery of the     

Expression and significance of E-cadherin,N-cadherin,transforming growth factor-β1 and Twist in prostate cancer

Objective:To study the expression of E-cadherin,N-cadherin,TGF-|3 1 and Twist protein and investigate its significance in the occurrence and development of prostate cancer.Methods:The expression of E-cadherin,N-cadherin,TGF-β1 and Twist protein in 59 prostate cancer tissues and 21 adjacent tissues were detected by immunohistochemical SABC staining,and the correlation with clinicopathological features was analyzed.Results:Positive rates of E-cadherin,N-cadherin,TGF-β1 and Twist were 32.2%,54.2%,71.2%and 74.6%,respectively,in prostate cancer tissues and 85.7%,9.52%,19.0%and 9.52%,respectively,in cancer—adjacent tissues,with significant differences between the two groups(P0.05).The reduced expression of E-cadherin was related to the differentiation of prostate cancer tissues and PSA level,but was not associated with clinical stage,lymph node metastasis,bony metastasis and age.The increased expression of N-cadherin,TGF-β1 and Twist was related to the differentiation of prostate cancer tissues,clinical stage,lymph node metastasis,bony metastasis,but not to age.The difference in positive expression of N-cadherin and TGF-β1 was significant between PSA≤20μg/L group and PSA20μg/L group,but the positive expression of Twist was not significant between groups.The expression of E-cadherin was highly negatively correlated with that of N-cadherin and also highly negatively correlated with that of Twist The expression of TGF-β1 was correlated with those of E-cadherin,N-cadherin and Twist.Conclusions:The reduced expression of E-cadherin,abnormal expression of N-cadherin,transformation form E-cadherin to N-cadherin and the increased expression of TGF-β1 and Twist play an important role in the occurrence and development of prostate cancer.     

Significance of expression of heat shock protein90α in human gastric cancer

AIM: To evaluate the significance of hsp90α expression in human gastric cancer tissues. METHODS: Immunohistochemical staining was used in clinical specimens from 33 cases of gastric cancer and 33 cases of gastritis with rabbit anti-human hsp90α multi-clonal antibody in order to explore the relationship between the expression of hsp90α in gastric carcinoma tissue and gastritis tissue as well as in mucous membrane adjacent to cancer and lymph node metastasis.RESULTS: Hsp90α was detected in 88% of gastric carcinoma cases and 55 % of gastritis cases. The hsp90α positive rate in gastric cancer group was significantly higher than that in gastritis group (P&lt;0.01, P=0.005). The hsp90α positive rate in gastric cancer and in mucous membrane adjacent to cancer was 88% and 55 % respectively (P&lt;0.01,P=0.005). The hsp90α positive rate in lymph node metastasis group and non-lymph node metastasis group was 100% and 60% respectively, and a significant correlation between hsp90α expression and lymph node metastasis was shown (P&lt;0.01,P=0.005). CONCLUSION: The hsp90α expression rate in gastric cancer group was significantly higher than that in gastritis group as well as that in the group of mucous membrane adjacent tocancer. The hsp90α expression in lymphatic node metastasis group was higher than that in non-lymphatic node metastasisgroup. The results indicate that increased hsp90α expression has a close relationship with occurrence and lymph node metastasis of gastric cancer.     

Expression of transforming growth factor-α and hepatitis B surface antigen in human hepatocellular carcinoma tissues and its significance

AIM:To evaluate the expression of transforming growthfactor-alpha (TGF-α) and hepatitis B surface antigen (HBsAg)in human hepatocellular carcinoma (HCC) tissues and itssignificance.METHODS:Seventy specimens of HCC tissues weredetected by immunohistochemical method.Five specimensof normal human liver tissues were used as control.RESULTS:The TGF-α positive expression rates in HCCand its surrounding tissues were 74.3%(52/70) and88.1%(52/59),respectively.TGF-α positive granules weremainly in the cytoplasm and fewer existed on thekaryotheca.The TGF-α positive expressing rate in welldifferentiated HCC was significantly higher than that inmoderately and poorly differentiated HCC (P<0.05).TheTGF-α positive expression also was observed in intrahepaticbile ducts (part of those were hyperplastic ducts).TheHBsAg positive expression rates in HCC and its surroundingtissues were 21.4%(15/70) and 79.7%(47/59),respectively.HBsAg positive granules were in the cytoplasm,inclusionand on the karyotheca.There was a prominent positivecorrelation between TGF-a and HBsAg expression in HCCsurrounding tissues (P<0.05,γ=0.34).TGF-α was usuallyexisted with HBsAg in regenerated and/or dysplastic livercells.In the five normal liver tissues,TGF-α and HBsAgwere not detectable in hepatocytes and bile ducts.CONCLUSION:Hepatitis B virus infection is closely relatedwith hepatocarcinogenesis.The overexpression of TGF-αin the liver seems to be associated with the regenerationof hepatocytes injured by HBsAg.The continued expressionof TGF-α might lead to dysplasia of liver cells anddevelopment of HCC.Furthermore,TGF-α might play arole in morphogenesis and regeneration of intrahepaticbile ducts.     

Antiangiogenic effects of ganetespib in colorectal cancer mediated through inhibition of HIF-1α and STAT-3

Hypoxia-inducible factors (HIFs) and STAT-3 play essential roles in angiogenesis. HIF-1α and STAT-3 are clients of the heat shock protein 90 (HSP90). We hypothesized that ganetespib, a potent HSP90 inhibitor, would disrupt angiogenesis in colorectal cancer (CRC) through inhibition of HIF-1α and STAT-3. CRC cell lines (HCT116 and HT29) were used in all the experiments. Egg CAM and HUVEC assays revealed decreased angiogenesis in ganetespib treated cell lines. Ganetespib inhibited matrigel plug vascularization and tumor growth of xenografts. Significant inhibition of PDGFA, FGF2, Ang-1, Ang-2, TGFβ1, VEGF, HIF-1α and STAT-3 expression was observed in both cell lines treated ganetespib. HIF-1α overexpression resulted in the increase VEGF and STAT-3 expression and this was inhibited by ganetespib. HIF-1α knockdown inhibited VEGF and STAT-3 expression. STAT-3 knockdown inhibited VEGF but not HIF-1α expression. HSP90, STAT-3 and VEGF expression was significantly higher in CRC compared to adjacent normal tissue. Significant downregulation of PDGFA, FGF2, Ang-1, Ang-2, TGFβ1, VEGF, STAT-3 and HIF-1α mRNA was observed in the post ganetespib treatment tumor samples from patients with rectal cancer. These results collectively suggest that inhibition of HSP90 is a promising antiangiogenic strategy in CRC. HSP90 angiogenic effects are mediated through HIF-1α and STAT-3.     

Has the risk of colorectal cancer in inflammatory bowel disease decreased?

The association between inflammatory bowel disease(IBD)and colorectal cancer(CRC)has been acknowledged for almost a century and is assumedly promoted by a chronic inflammation-driven carcinogenic process in the intestine in combination with a genetic predisposition.The magnitude of the risk of CRC in IBD remains a continuing subject of debate.The early,high risk estimates for CRC in IBD were most likely overestimated due to selected patient populations originating from tertiary referral centers with a disproportional high percentage of patients with severe disease.Later population-based studies calculating risk estimates from a broad spectrum of IBD patients have found the risk to be significantly lower.At present,there is evidence that IBD patients with longstanding and extensive disease with uncontrolled inflammation are those at increased risk.Additional,other recognized risk factors include early age at onset,family history of CRC,and concomitant primary sclerosing cholangitis.A significant amount of effort is put into identifying potential preventive factors of CRC in IBD,including surveillance programs and chemopreventive agents but the individual effect of these remains uncertain.Interestingly,recent studies have reported a decline in risk of CRC over time.Surveillance programs and the new treatment strategies,particular biological treatment might be part of the reason for the observed decline in risk of CRC in IBD over time but future studies will have investigate this assumption.