Hypermethylated in cancer 1(HIC1) suppresses non-small cell lung cancer progression by targeting interleukin-6/Stat3 pathway.

Xiumin Wang,Xueqing Sun,Jianhua Wang,Guohong Hu,Jinglong Wang,Yingying Wang,Yujie Fu,Lidong Zu,Gang Xiao,Mingang Hao

doi:10.18632/oncotarget.8734

Abstract

Non-small cell lung cancer (NSCLC), which accounts for more than 80% of lung cancers, is a leading cause of cancer mortality worldwide. However, the mechanism underlying its progression remains unclear. Here we found that HIC1 promoter was heavily methylated in NSCLC cell lines and tissues contributing to its low expression compared to normal controls. Restoring HIC1 expression inhibited migration, invasion and promoted inducible apoptosis of NSCLC cells. Notably, HIC1 is a tumor suppressor through inhibiting the transcription of IL-6 by sequence-specific binding on its promoter. Restoring IL-6 expression could partially rescue these phenotypes induced by HIC1 in vitro and in vivo. Mechanistic analyses show that autocrine secretion of IL-6 induced by loss of HIC1 activated STAT3 through IL-6/JAK pathway and was associated with NSCLC progression. The HIC1/IL-6 axis may serve as a prognostic biomarker and provide an attractive therapeutic target for NSCLC.

Highlights

Lung cancer is the leading cause of cancer mortality worldwide, accounting for 1.6 million deaths according to the latest statistics [1]
To examine whether HIC1 is inactive by hypermethylation in Non-small cell lung cancer (NSCLC), we examined the methylation status of HIC1 promoter in cell lines and 10 pairs of NSCLC carcinoma and para-carcinoma tissues by methylation specific PCR (MSP) and bisulfite sequencing PCR (BSP) (Figure 1A, 1B and 1C)
The results show that HIC1 expression was lower in H292, 95-D, A549, NCI-H1975 and LTEP-a-2 cells (Figure 1D) and carcinoma tissues (Figure 1E) than in MRC-5, WI-38 cells and para-carcinoma tissues respectively

Summary

Introduction

Lung cancer is the leading cause of cancer mortality worldwide, accounting for 1.6 million deaths according to the latest statistics [1]. Distant metastases in patients with lung cancer are the leading cause of death [3]. It is significant to identify novel metastases-related genes in lung cancer, especially in NSCLC, which may become useful biomarkers for the early detection or attractive targets for treatment. Hypermethylated in cancer 1(HIC1) is a gene located at 17p13.3 and can be activated by p53, which was first identified by Baylin in 1995 [8]. This finding indicates that HIC1 expression is absent or decreased in neoplastic cells, which have the aberrant pattern of HIC1 CpG island NotI site methylation. Increasing evidence shows that HIC1 is aberrantly hypermethylated in multiple common types of human cancer tissues, including breast [9, 10], medulloblastomas [11, 12], gastric [13], hepatocellular carcinoma [14], colorectal [15], cervical [16] and lung tumors [17]

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Conclusion