Abstract
BackgroundHyaluronan synthases (HAS) control the biosynthesis of hyaluronan (HA) and critically modulate the tumor microenviroment. Cancer-associated fibroblasts (CAFs) affect the progression of a tumor by remolding the matrix. However, little is known about the role of HAS from CAFs in this process. This study aimed to determine the role of hyaluronan synthase 2 (HAS2) from CAFs in the progression of oral squamous cell carcinoma (OSCC) invasion.MethodsHAS isoforms 1, 2, and 3 in paired sets of CAFs and normal fibroblasts (NFs) were examined by real-time PCR, and the expression of HAS2 and α-SMA in OSCC tissue sections was further evaluated using immunohistochemical staining. Furthermore, we used a conditioned culture medium model to evaluate the effects of HAS2 from CAFs on the invasion and epithelial-mesenchymal transition (EMT) of the oral cancer cells Cal27. Finally, we compared the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) between CAFs and NF, and between CAFs with or without HAS2 knockdown using an antibody array and western blotting.ResultsCAFs expressed higher levels of HAS2 than the paired NFs. HAS2 expression was consistent with α-SMA-positive myofibroblasts in the stroma of OSCC, and these were significantly correlated advanced clinical stages and cervical lymph node metastasis. Knocking down HAS2 with a specific siRNA or treatment with a HAS inhibitor markedly attenuated CAF-induced invasion and EMT of Cal27 cells. Higher MMP1 and lower TIMP1 levels were detected in the supernatants of CAFs relative to NFs. Knocking down HAS2 could decrease the expression of MMP1 and increase that of TIMP1 in CAFs.ConclusionsHAS2 is one of the key regulators responsible for CAF-mediated OSCC progression and acts by modulating the balance of MMP1 and TIMP1.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0458-0) contains supplementary material, which is available to authorized users.
Highlights
Hyaluronan synthases (HAS) control the biosynthesis of hyaluronan (HA) and critically modulate the tumor microenviroment
Our findings indicated that hyaluronan synthase 2 (HAS2) is one of the key regulators responsible for Cancer-associated fibroblasts (CAFs)-mediated oral squamous cell carcinoma (OSCC) progression and that it acts by modulating the balance between MMP1 and TIMP1
HAS2 expression is higher in CAFs than in normal fibroblasts (NFs) To determine the abundance of HAS isoforms in CAFs from OSCCs and the paired NFs from the same patients, fresh OSCC samples were acquired from three patients by macroscopic dissection using the following morphological mapping: CAFs from the actual tumors were isolated from the epicenter of the tumor tissue, and the matched NFs were isolated from distal normal tissue located at least 10 mm from the tumor margins
Summary
Hyaluronan synthases (HAS) control the biosynthesis of hyaluronan (HA) and critically modulate the tumor microenviroment. This study aimed to determine the role of hyaluronan synthase 2 (HAS2) from CAFs in the progression of oral squamous cell carcinoma (OSCC) invasion. Oral squamous cell carcinoma (OSCC) is prone to metastasis through lymphatic channels, which leads to cancer-related mortality and an unfavorable prognosis [1]. During this intricate process, the malignant epithelial cells interact with the adjacent stromal cells and the extracellular matrix (ECM) to support their migration and invasion. Cancer-associated fibroblasts (CAFs), which are known as myofibroblasts and are characterized by αsmooth muscle actin (α-SMA) expression, are the stromal cells involved in producing a tumor cell niche in coordination with other cell types such as macrophages to fuel cancer overgrowth and spreading [2]. The underlying mechanisms that are responsible for CAFmediated OSCC dissemination remain unknown
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