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

Lui Ka Yin¹， Zhao Hui¹， Qiu Chunhui¹， Li Chuo¹， Tang Baiyun¹， Zhang Zhigang¹， Peng Haoran¹， Fu Rongdang¹， Chen Huan¹， Lu Minqiang²

目的: Integrator complex subunit 6 (INTS6) was found to play a tumor suppressive role in certain types of solid tumors. In this study, we wanted to investigate the expression of INTS6 in hepatocellular carcinoma (HCC) and evaluated the clinical characteristic and mechanism in HCC patients.

方法: Firstly, the expression level of mRNA in the HCC and paired normal liver tissues by using the microarray analysis; Secondly, the expression level of INTS6 mRNA were measured in a cohort of 50 HCC tissues and adjacent normal liver tissues by using the qRT-PCR; Thirdly, the expression level of INTS6 protein were detected in 20 paired HCC and corresponding adjacent normal tissue by using western blot; Fourthly, Immunohistochemistry was performed on 70 archived paraffin-embedded HCC samples. At last, we investigated its suppressive function in Wnt pathway.

结果: Herein, according to the microarray data analysis, the expression level of INTS6 has been shown to be dramatically down-regulated in HCC vs. that in normal liver tissues (p<0.05). qRT-PCR and western blot analyses showed the INTS6 mRNA and protein expression was significantly down-regulated in tumor tissues compared to 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 (AFP, p =0.004), pathology grade (p =0.005), and tumor recurrence (p =0.04). Kaplan-Meier analysis revealed that patients with low INTS6 expression levels had a shorter overall and disease-free survival than patients with
high expression (p =0.001 and p =0.001). Multivariate regression analysis indicated that INTS6 was an independent predictor for overall survival and disease-free survival. Mechanistically, INTS6 increased WIF-1 expression and then inhibited the Wnt/β- catenin signaling pathway.

结论: The results of our study showed that down-regulated INTS6 expression was associated with poorer prognosis in HCC patients. This newly identified INTS6/WIF-1 axis indicated the molecular mechanism of HCC and maybe represented a therapeutic target in HCC patients.