HIC-5 in cancer-associated fibroblasts contributes to esophageal squamous cell carcinoma progression

Xuanling Du,Xiaobo Li,Dongke Xu,Shiyao Chen,Rui Zhang,Duyi Pan,Qiping Xu,Wenting Hong,Baolin Niu

doi:10.1038/s41419-019-2114-z

Abstract

Esophageal squamous cell carcinoma (ESCC) remains one of the most common malignancies in China and has a high metastasis rate and poor prognosis. Cancer-associated fibroblasts (CAFs), a prominent component of the tumor microenvironment, can affect tumor progression and metastasis, but the underlying mechanism remains unclear. There are no studies that explore the role of hydrogen peroxide-inducible clone 5 (HIC-5) in ESCC or compare the role of HIC-5 in CAFs and adjacent noncancerous normal fibroblasts (NFs). In this study, we isolated primary CAFs and NFs from ESCC patients. HIC-5 was highly expressed in CAFs from the tumor stroma of human ESCC patients. HIC-5 knockdown in CAFs inhibited the migration and invasion of ESCC cells in vitro. Supernatant CCL2 levels of CAFs were significantly higher after TGF-β stimulation and lower after knocking down HIC-5 expression, independent of TGF-β treatment. HIC-5 knockdown in CAFs led xenograft tumors derived from ESCC cells mixed with CAFs to present more regular morphology, express higher CDH1, and lower CCL2. Further RNA-seq data showed that HIC-5 has distinct biological functions in CAFs vs. NFs, especially in cell movement and the Rho GTPase signaling kinase pathway, which was verified by wound-healing assays and western blotting. An ESCC tissue microarray revealed that increased HIC-5 expression in the tumor stroma was associated with positive lymph node metastasis and a higher TNM stage. In summary, we identified that stromal HIC-5 was a predictive risk factor for lymph node metastasis in human ESCC and that CAF-derived HIC-5 regulated ESCC cell migration and invasion by regulating cytokines and modifying the ECM.

Highlights

Esophageal cancer, one of the most common malignancies, has a global incidence and mortality ranking of 7th and 6th, respectively, and it has the third lowest 5year relative survival rate of all cancers.[1]
(see figure on previous page) Fig. 1 hydrogen peroxide-inducible clone 5 (HIC-5) is highly expressed in Cancer-associated fibroblasts (CAFs) from human esophageal squamous cell carcinoma (ESCC) tumor stroma. a Representative images of hematoxylin–eosin staining and HIC-5 staining in esophageal squamous cell cancer tissue and adjacent non-tumor tissue (scale bar, 500 μm and 200 μm)
We demonstrated that HIC-5 was highly expressed in tumor stroma of human ESCC, and CAFderived HIC-5 contributed to esophageal cancer cell migration and invasion

Summary

Introduction

Esophageal cancer, one of the most common malignancies, has a global incidence and mortality ranking of 7th and 6th, respectively, and it has the third lowest 5year relative survival rate of all cancers.[1] China, one of the countries with the highest esophageal cancer and esophageal squamous cell carcinoma (ESCC) are two major esophageal cancer subtypes. ESCC accounts for 88.84% of all cases in China, which is different from the pattern in western countries where EAC is much more common.[3,4] The disease is metastatic in over 60%. Of newly diagnosed cases, which is one of the principal reasons why the overall 5-year survival rate of esophageal cancer is

Methods

Results

Conclusion