Gene expression profiling-derived immunohistochemistry signature with high prognostic value in colorectal carcinoma.

OBJECTIVE: Gene expression profiling provides an opportunity to develop robust prognostic markers of colorectal carcinoma (CRC). However, the markers have not been applied for clinical decision making. We aimed to develop an immunohistochemistry signature using microarray data for predicting CRC prognosis. DESIGN: We evaluated 25 CRC gene signatures in independent microarray datasets with prognosis information and constructed a subnetwork using signatures with high concordance and repeatable prognostic values. Tumours were examined immunohistochemically for the expression of network-centric and the top overlapping molecules. Prognostic values were assessed in 682 patients from Shanghai, China (training cohort) and validated in 343 patients from Guangzhou, China (validation cohort). Median follow-up duration was 58 months. All p values are two-sided. RESULTS: Five signatures were selected to construct a subnetwork. The expression of GRB2, PTPN11, ITGB1 and POSTN in cancer cells, each significantly associated with disease-free survival, were selected to construct an immunohistochemistry signature. Patients were dichotomised into high-risk and low-risk subgroups with an optimal risk score (1.55). Compared with low-risk patients, high-risk patients had shorter disease-specific survival (DSS) in the training (HR=6.62; 95% CI 3.70 to 11.85) and validation cohorts (HR=3.53; 95% CI 2.13 to 5.84) in multivariate Cox analyses. The signature better predicted DSS than did tumour-node-metastasis staging in both cohorts. In those who received postoperative chemotherapy, high-risk score predicted shorter DSS in the training (HR=6.35; 95% CI 3.55 to 11.36) and validation cohorts (HR=5.56; 95% CI 2.25 to 13.71). CONCLUSIONS: Our immunohistochemistry signature may be clinically practical for personalised prediction of CRC prognosis.

Nuclear orphan receptor NR4A2 confers chemoresistance and predicts unfavorable prognosis of colorectal carcinoma patients who received postoperative chemotherapy.

BACKGROUND: NR4A2, an orphan nuclear receptor essential in neuron generation, has been recently linked to inflammatory and metabolic pathways of colorectal carcinoma (CRC). However, the effects of NR4A2 on chemo-resistance and postoperative prognosis of CRC remain unknown. METHODS: NR4A2 was transfected into CRC cells to investigate its effects on chemo-resistance to 5-fluorouracil and oxaliplatin and chemotherapeutics-induced apoptosis. We also investigated prostaglandin E2 (PGE2)-induced NR4A2 expression and its effect on chemo-resistance. Tissue microarrays including 51 adenoma, 14 familial adenomatous polyposis with CRC, 17 stage IV CRC with adjacent mucosa and 682 stage I-III CRC specimens were examined immunohistochemically for NR4A2 expression. Median follow-up time for stage I-III CRC patients was 53 months. RESULTS: Ectopic expression of NR4A2 increased the chemo-resistance, and attenuated the chemotherapeutics-induced apoptosis. Transient treatment of PGE2 significantly up-regulated NR4A2 expression via protein kinase A pathway and increased the chemo-resistance. NR4A2 expression in epithelials consecutively increased from adenoma, adjacent mucosa to CRC (P(trend)<0.001). In multivariate Cox regression analyses, high NR4A2 expression in cancer nuclei (immunoreactive score ≥ 4) significantly predicted a shorter disease-specific survival (DSS) of CRC patients (hazard ratio [HR]=1.88, P=0.024). High NR4A2 expression specifically predicted a shorter DSS of colon cancer patients (dichotomisation, HR=2.55, log-rank test P=0.011), especially for those who received postoperative 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) chemotherapy (3-score range, HR=1.86, log-rank test P=0.020). CONCLUSION: High expression of NR4A2 in CRC cells confers chemo-resistance, attenuates chemotherapeutics-induced apoptosis, and predicts unfavorable prognosis of colon cancer patients, especially for those who received postoperative chemotherapy. NR4A2 may be prognostic and predictive for colon cancer.

Risk factor for clear cell renal cell carcinoma in Chinese population: a case-control study.

BACKGROUND: Risk factors for clear cell renal cell carcinoma (ccRCC) differ among populations and remain controversial. We carried out a hospital-based case-control study to examine the effects of health status, lifestyle, and some genetic polymorphisms on ccRCC risk in Chinese subjects. METHODS: Between 2007 and 2009, 250 newly diagnosed, histologically confirmed ccRCC cases and 299 sex-, age-matched healthy controls provided complete information including consumption of tea and alcohol, smoking, occupational exposure, body mass index (BMI), hypertension, diabetes, and urolithiasis by face-to-face interview in Shanghai. Genetic polymorphisms of cytochrome P450 mono-oxygenase (CYP1A1: 6235T>C, 4889A>G, and 4887C>A), glutathione S-transferase (GSTP1: 342A>G), and N-acetyltransferase (NAT2: 481C>T, 590G>A, and 857G>A) were identified by PCR-RFLP and DNA sequencing. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were derived through multivariate logistic regression. RESULTS: Green tea intake (≥500 ml/d) was inversely associated with ccRCC risk, with an AOR of 0.34 (95% CI 0.21-0.55). BMI (≥25 kg/m(2)), hypertension, and urolithiasis were independently associated with an increased risk of ccRCC, with AOR (95% CI) of 2.10 (1.32-3.34), 2.49 (1.57-3.93), and 3.33 (1.12-9.89), respectively. No association was observed between smoking, alcohol consumption, or occupational exposure with ccRCC risk. The polymorphisms and their interactions with the environmental exposures were mostly not associated with ccRCC risk. CONCLUSION: BMI (≥25 kg/m(2)), hypertension, and urolithiasis are independently associated with an increased risk, whereas green tea intake (≥500 ml/d) is independently associated with a decreased risk of ccRCC. The polymorphisms of the xenobiotic-metabolizing enzymes are weakly associated with ccRCC risk in Chinese subjects.

USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha.

IkappaBalpha serves as a central anchoring molecule in the sequestration of NF-kappaB transcription factor in the cytoplasm. Ubiquitination-mediated IkappaBalpha degradation immediately precedes and is required for NF-kappaB nuclear translocation and activation. However, the precise mechanism for the deubiquitination of IkappaBalpha is still not fully understood. Using a proteomic approach, we have identified Ubiquitin Specific Peptidase 11 (USP11) as an IkappaBalpha associated deubiquitinase. Overexpression of USP11 inhibits IkappaBalpha ubiquitination. Recombinant USP11 catalyzes deubiquitination of IkappaBalpha in vitro. Moreover, knockdown of USP11 expression enhances TNFalpha-induced IkappaBalpha ubiquitination and NF-kappaB activation. These data demonstrate that USP11 plays an important role in the downregulation of TNFalpha-mediated NF-kappaB activation through modulating IkappaBalpha stability. In addition, overexpression of a catalytically inactive USP11 mutant partially inhibits TNFalpha- and IKKbeta-induced NF-kappaB activation, suggesting that USP11 also exerts a non-catalytic function in its negative regulation of TNFalpha-mediated NF-kappaB activation. Thus, IkappaBalpha ubiquitination and deubiquitination processes function as a Yin-Yang regulatory mechanism on TNFalpha-induced NF-kappaB activation.

Comparison of hypertension, dyslipidaemia and hyperglycaemia between buckwheat seed-consuming and non-consuming Mongolian-Chinese populations in Inner Mongolia, China.

1. In the present study, a total of 3542 Mongolians in two adjacent counties of Inner Mongolia, China, were randomly sampled in a cross-sectional study to assess the association of hypertension, dyslipidaemia and hyperglycaemia with lifetime consumption of buckwheat seed as a staple food. A sample group of 961 participants was also examined for fasting serum concentrations of lipids and glucose. 2. Frequent alcohol consumption significantly contributed to the high prevalence rate of hypertension in the pastureland Mongolian population. 3. The age-adjusted prevalence rate of hypertension in Kulun participants who consumed buckwheat seed as a staple food was 18.22% (95% confidence interval (CI): 16.95%, 19.49%), whereas that in Kezhuohou participants, who consumed corn as a staple food, was 23.31% (95% CI: 21.92%, 24.70%). A statistically significant difference was found between the two groups (P < 0.01). 4. Age-adjusted prevalence rates in Kulun participants compared with Kezhuohou participants for hypercholesterolaemia, hypertriglyceridaemia and abnormalities in low-density lipoprotein-cholesterol were 4.02% (95% CI: 2.24%, 5.80%) versus 7.76% (95% CI: 5.39%, 10.13%; P < 0.01), 26.58% (95% CI: 22.59%, 30.57%) versus 31.04% (95% CI: 26.59%, 35.13%; P < 0.05) and 4.66% (95% CI: 2.75%, 6.57%) versus 8.81% (95% CI: 6.30%, 11.32%; P < 0.01), respectively. 5. The age-adjusted prevalence rate of hyperglycaemia in Kulun participants was 1.56% (95% CI: 0.78%, 2.34%), whereas that in Kezhuohou participants was 7.70% (95% CI: 6.01%, 9.39%). The difference was significant (P < 0.01). 6. These findings suggest that the consumption of buckwheat seed may be a preventative factor for hypertension, dyslipidaemia and hyperglycaemia in the pastureland Mongolian population.