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

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.

Uveal Melanoma Cells Elicit Retinal Pericyte Phenotypical and Biochemical Changes in an in Vitro Model of Coculture

“…As tumor activation of fibroblasts triggers both high migration and proliferation rates in patients and in animal models [ 52 , 53 ], we next aimed to evaluate the migratory ability and proliferation rate in pericytes after 6 days of interaction with 92.1UM cells. For this reason, a wound-healing assay was performed at the end of the conditioning period as described in the Materials and Methods section.…”

Underlying mechanisms and drug intervention strategies for the tumour microenvironment

“…In detail, peritoneal macrophages support angiogenesis and cancer growth through the production of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) [ 47 ]. Similarly, CAFs-derived hydrogen peroxide-induced clone 5 (HIC-5) regulates cytokines and modifies the ECM to regulate the invasion of oesophageal squamous cell carcinoma (ESCC) cells [ 48 ].…”

Therapeutic Potential of Reactive Oxygen Species: State of the Art and Recent Advances

“…It is activated by both ROS and TGF-β 100 and is associated with the progression of several cancers. 101–105…”