Integrator complex subunit 6 (INTS6) inhibits hepatocellular carcinoma growth by Wnt pathway and serve as a prognostic marker.

BACKGROUND: Integrator complex subunit 6 (INTS6) was found to play a tumour suppressing role in certain types of solid tumours. In this study, we wanted to determine the expression level of INTS6 in hepatocellular carcinoma (HCC) and evaluate its clinical characteristics and mechanisms in HCC patients (Lui and Lu, European Journal of Cancer, 51:S94, 2015). METHODS: First, we used a microarray analysis to explore the mRNA expression levels in HCC and paired normal liver tissues; second, we used qRT-PCR to measure the INTS6 mRNA levels in a cohort of 50 HCC tissues and adjacent normal liver tissues; third, we used Western blot analyses to detect the INTS6 protein levels in 20 paired HCC and normal liver tissues; fourth, we used immunohistochemistry to determine the INTS6 expression levels in 70 archived paraffin-embedded HCC samples. Finally, we investigated the suppressive function of INTS6 in the Wnt pathway. RESULTS: Herein, according to the microarray data analysis, the expression levels of INTS6 were dramatically down-regulated in HCC tissues vs. those in normal liver tissues (p<0.05). qRT-PCR and Western blot analyses showed that the INTS6 mRNA and protein expression was significantly down-regulated in tumour tissues compared to the adjacent normal liver tissues (p<0.05). Immunohistochemical assays revealed that decreased INTS6 expression was present in 62.9% (44/70) of HCC patients. Correlation analyses showed that INTS6 expression was significantly correlated with serum alpha-fetoprotein levels (AFP, p =0.004), pathology grade (p =0.005), and tumour recurrence (p =0.04). Kaplan-Meier analysis revealed that patients with low INTS6 expression levels had shorter overall and disease-free survival rates than patients with high INTS6 expression levels (p =0.001 and p =0.001). Multivariate regression analysis indicated that INTS6 was an independent predictor of overall survival and disease-free survival rates. Mechanistically, INTS6 increased WIF-1 expression and then inhibited the Wnt/ß-catenin signalling pathway. CONCLUSION: The results of our study show that down-regulated INTS6 expression is associated with a poorer prognosis in HCC patients. This newly identified INTS6/WIF-1 axis indicates the molecular mechanism of HCC and may represent a therapeutic target in HCC patients.

Pseudogene integrator complex subunit 6 pseudogene 1 (INTS6P1) as a novel plasma-based biomarker for hepatocellular carcinoma screening.

In this study, we aimed to determine whether the pseudogene integrator complex subunit 6 pseudogene 1 (INTS6P1) in plasma could be used as a novel approach to screen for and detect hepatocellular carcinoma (HCC). We explored the clinical role of INTS6P1: First, the expression level of INTS6P1 was measured in a cohort of 33 HCC tissue samples and adjacent normal liver tissue, next, the INTS6P1 expression was detected in the culture medium and tumor cells in a cellular experiment, and last, the diagnostic performance of INTS6P1 was examined in an independent cohort of 100 people. The expression level of INTS6P1 was remarkably downregulated in the HCC tissues compared with that in the normal liver tissues (p = 0.0066). In plasma, the INTS6P1 levels were significantly decreased in HCC patients compared with non-HCC patients (p < 0.01). Additionally, we inferred that INTS6P1 might be a prospective biomarker for screening HCC patients in which the serum-AFP levels were lower than 20 ng/ml by the area under the curve-receiver operating characteristic (AUC-ROC) analysis (p < 0.05). Pseudogene INTS6P1 could be used as a novel HCC plasma-based biomarker and might improve the accuracy of HCC screening.

Retinoic acid receptor-related receptor alpha (RORalpha) is a prognostic marker for hepatocellular carcinoma.

Retinoic acid receptor-related receptor alpha (RORalpha) has been proven to play a tumor suppressive role in certain types of solid tumors. However, the clinical characteristic of RORalpha has not been reported by far. This study investigated the expression of RORalpha in hepatocellular carcinoma (HCC) and evaluated its relationship with clinical parameters and prognosis in HCC patients. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot analyses were performed to detect RORalpha expression levels in 20 paired HCC and corresponding adjacent non-cancerous tissues. Immunohistochemistry was performed on 100 archived paraffin-embedded HCC samples. Statistical analyses evaluated the correlations between RORalpha expression and clinicopathological features. qRT-PCR showed that RORalpha mRNA expression was significantly down-regulated in tumors compared to the adjacent non-cancerous tissues, and Western blots found that RORalpha protein expression was also reduced in tumor tissues. Immunohistochemical assays revealed that decreased RORalpha expression was present in 65 % of HCC patients. Correlation analyses showed that RORalpha expression was significantly correlated with serum alpha fetoprotein (AFP, p = 0.005), pathology grade (p < 0.001), tumor recurrence (p = 0.008), and vascular invasion (p < 0.001). Kaplan-Meier analysis revealed that patients with low RORalpha expression levels had a shorter overall and disease-free survival than patients with high expression (p < 0.001 and p = 0.002, respectively). Multivariate regression analysis indicated that RORalpha was an independent predictor for overall survival and disease-free survival. In conclusion, the results of our study showed that down-regulated RORalpha expression was associated with poorer prognosis in HCC patients. RORalpha may be a new potential prognostic marker for HCC patients.

[Model for end-stage liver disease-sodium predicts prognosis in patients with chronic severe hepatitis B].

OBJECTIVES: To study the practical use of the serum sodium incorporated model for end-stage liver disease (MELD-Na) on clinic and to assess its validity by the concordance-statistic in predicting the prognosis of the patients with chronic severe hepatitis B. METHODS: Adult patients with a diagnosis of chronic severe hepatitis B between January 2007 and December 2007 in a single center were analyzed. The serum sodium, MELD, MELD-Na, and Delta MELD-Na (Delta MELD=MELD score at 14 days after medical treatment-MELD score at admission) scores of 426 patients with chronic severe hepatitis B were calculated. The 3-month mortality in patients was measured, and the validity of the models was determined by means of the concordance-statistic. RESULTS: The area under the receiver-operating characteristic curves of Na, MELD and MELD-Na for the occurrence of death in 3 month were 0.718, 0.875 and 0.922. The 3-month mortality of the MELD-Na scores group <25, 25-30, >30-35, >35- <40 and > or = 40 were 2.0%, 5.4%, 35.4%, 53.8% and 86.9% respectively. There was a significant difference of 3-month mortality between the five groups (P<0.05). The 3-month mortality of Delta MELD-Na> 0 group was 65.9%, and the Delta MELD-Na < or = 0 group was 15.8%. There was a significant difference of 3-month mortality between the two groups (P<0.05). CONCLUSIONS: MELD-Na score is a valid model to predict 3-month mortality in patients with chronic severe hepatitis B. Delta MELD-Na is clinically useful parameters for predicting the therapeutic effect of chronic severe hepatitis B.

Model for end-stage liver disease-sodium predicts prognosis in patients with chronic severe hepatitis B.

BACKGROUND: Serum sodium predicts prognosis in chronic severe hepatitis B and may improve the prognostic accuracy of the model for end-stage liver disease (MELD) score, but the available information is limited. The present study was undertaken to study the clinical use of the serum sodium incorporated MELD (MELD-Na) and assess its validity by the concordance (c)-statistics in predicting the prognosis of the patient with chronic severe hepatitis B. METHODS: A total of 426 adult patients with a diagnosis of chronic severe hepatitis B between January 1, 2007, and December 31, 2007 at a single center were studied. The scores of serum sodium, MELD, MELD-Na, and DeltaMELD-Na (DeltaMELD-Na = MELD-Na at 14 days after medical treatment -MELD-Na score on admission) of the patients with chronic severe hepatitis B were calculated. The 3-month mortality in the patients was measured, and the validity of the models was determined by means of the concordance (c) statistics. RESULTS: The average MELD, MELD-Na scores of survival group were 25.70 +/- 5.08 and 26.60 +/- 6.90, and those of dead group were 35.60 +/- 6.78 and 42.80 +/- 9.57 on admission. There was a significant difference in MELD and MELD-Na between the survival and dead groups (P < 0.01). The average DeltaMELD-Na score of the survival group was -0.97 +/- 3.51, and that of the dead group was 3.45 +/- 2.38 at 2 weeks after the treatment. There was a significant difference in DeltaMELD-Na between the survival and dead groups (P < 0.01). The areas under the receiver-operating characteristic curves of Na, MELD and MELD-Na for the occurrence of death in 3 months were 0.742, 0.875 and 0.922. The 3-month mortality of the MELD-Na scores group < 25, 25-30, 31-34, 35-40 and > 40 were 2.0%, 5.4%, 35.4%, 53.8 % and 86.9%, respectively. There was a significant difference in the 3-month mortality between the five groups (P < 0.05). The 3-month mortality of the DeltaMELD-Na > 0 group was 65.9%, and that of the DeltaMELD-Na = 0 group was 15.8%; there was a significant difference in the 3-month mortality between the two groups (P < 0.05). CONCLUSIONS: MELD-Na score is a valid model to predict the 3-month mortality in patients with chronic severe hepatitis B. DeltaMELD-Na is a clinically useful parameter for predicting the therapeutic effect of chronic severe hepatitis B.

[An evaluation of the prognosis of patients with chronic severe hepatitis using a model for end-stage liver disease].

OBJECTIVE: To investigate the prognosis evaluation and treatment strategy of chronic severe hepatitis (CSH) patients using a model of end-stage liver disease (MELD). METHODS: The MELD scores of 135 CSH patients on the day of their admittance to our hospital and the DeltaMELD scores after two-weeks of medical treatment were retrospectively analyzed. They were also compared with the scores of the three-month mortality rate of the patients. RESULTS: The mean MELD score calculated on the first day of the patients who died after their admission to the hospital was 37.00+/-6.50, while that of the living group was 25.80+/-5.20. The difference was highly significant (chi(2)=72.00, P < 0.01). MELD score after two-weeks medical treatment of the patients who died was 1.57+/-0.89, while that of the living group was -0.99+/-0.73; the difference was also highly significant (chi(2)=56.35, P < 0.01). The area under the ROC curve of MELD score (c-statistic) was 0.90, while the c-statistic for DeltaMELD score was 0.76. On the first day of their admission, when the MELD score was < 25, the three-month mortality rate was 2%; when it was 25 or= 35, the three-month mortality rate was 81%; the differences between these groups were all highly significant (P less than 0.01). When MELD scores were above zero, the three-month mortality was 51%, and when DeltaMELD scores were less than or equal to zero, the three-month mortality rate was 13%. All the differences were highly significant (P < 0.01). CONCLUSION: A high MELD score and a high Delta MELD score herald high three-month mortality rates in patients with CSH. MELD is quite usable in assessing the prognosis in patients suffering CSH. The choice of treatment for the CSH patients could be made by integrating the MELD score calculated on the first day of being admitted to a hospital and the Delta MELD score after their medical treatment.