Full-length soluble CD147 promotes MMP-2 expression and is a potential serological marker in detection of hepatocellular carcinoma

Abstract

BackgroundAs a surface glycoprotein, CD147 is capable of stimulating the production of matrix metalloproteinases (MMPs) from neighboring fibroblasts. The aim of the present study is to explore the role of soluble CD147 on MMPs secretion from hepatocellular carcinoma (HCC) cells, and to investigate the diagnostic value of serum soluble CD147 in the HCC detection.MethodsWe identified the form of soluble CD147 in cell culture supernate of HCC cells and serum of patients with HCC, and explored the role of soluble CD147 on MMPs secretion. Serum CD147 levels were detected by the enzyme-linked immunosorbent assay, and the value of soluble CD147 as a marker in HCC detection was analyzed.ResultsFull length soluble CD147 was presented in the culture medium of HCC cells and serum of patients with HCC. The extracellular domain of soluble CD147 promoted the expression of CD147 and MMP-2 from HCC cells. Knockdown of CD147 markedly diminished the up-regulation of CD147 and MMP-2 which induced by soluble CD147. Soluble CD147 activated ERK, FAK, and PI3K/Akt pathways, leading to the up-regulation of MMP-2. The level of soluble CD147 in serum of patients with HCC was significantly elevated compared with healthy individuals (P < 0.001). Soluble CD147 levels were found to be associated with HCC tumor size (P = 0.007) and Child-Pugh grade (P = 0.007). Moreover, soluble CD147 showed a better performance in distinguishing HCC compared with alpha-fetoprotein.ConclusionsThe extracellular domain of soluble CD147 enhances the secretion of MMP-2 from HCC cells, requiring the cooperation of membrane CD147 and activation of ERK, FAK, and PI3K/Akt signaling. The measurement of soluble CD147 may offer a useful approach in diagnosis of HCC.

Plasma soluble cluster of differentiation 147 levels are increased in breast cancer patients and associated with lymph node metastasis and chemoresistance

“…Moreover, serum sCD147 was elevated in patients with hepatocellular carcinoma compared with healthy individuals, and sCD147 level was associated with tumour size and Child-Pugh score. 15 Gross et al 22 also reported that sCD147 levels were elevated in patients with multiple myeloma, and elevated levels were associated with refractory disease and shortened progression-free survival, indicating that sCD147 may be a new prognostic factor for patients with multiple myeloma.…”

“…[28][29][30][31] Tumour cells express molecules, either secreted or presented on the cell surface, that interact with surrounding stromal cells. Soluble CD147 may be released from membrane-associated CD147 as a result of both MMP proteolytic Abbreviations: ER = oestrogen receptor; HER2 = human epidermal growth factor receptor 2; PR = progesterone receptor * Exact tumour size could not be determined for four patients Abbreviations: CI = confidence interval; HER2 = human epidermal growth factor receptor 2; sCD147 = soluble cluster of differentiation 147; SE = standard error Wu et al 15 reported that serum sCD147 enhances the secretion of MMP-2 from hepatocellular carcinoma cells by activating extracellular signal-regulated kinase and focal adhesion kinase, as well as phosphoinositide-3-kinase/Akt signalling, indicating that sCD147 may contribute to hepatocellular carcinoma progression. Moreover, serum sCD147 was elevated in patients with hepatocellular carcinoma compared with healthy individuals, and sCD147 level was associated with tumour size and Child-Pugh score.…”

“…[15][16][17] Overexpression of the CD147 gene in human breast cancer cells can increase the sCD147 level, indicating that sCD147 release is correlated with the degree of CD147 expression in tumour cells. [15][16][17] Full-length CD147 may be exported into the microenvironment from tumour cells by microvesicle shedding or by matrix metalloproteinase (MMP)-dependent cleavage, thereby stimulating MMP expression in fibroblasts.…”

“…[15][16][17] Overexpression of the CD147 gene in human breast cancer cells can increase the sCD147 level, indicating that sCD147 release is correlated with the degree of CD147 expression in tumour cells. [15][16][17] Full-length CD147 may be exported into the microenvironment from tumour cells by microvesicle shedding or by matrix metalloproteinase (MMP)-dependent cleavage, thereby stimulating MMP expression in fibroblasts. [18][19][20] In turn, sCD147 derived from tumour cells acts in a paracrine fashion on stromal cells that are both adjacent and distant to tumour sites, so as to further stimulate the production of MMPs and CD147.…”

“…16,21 Importantly, several studies investigating the role of sCD147 level in patients with tumours have suggested that sCD147 may offer a useful approach in diagnosis, as it is correlated with disease severity. 15,22 However, little is known about the level of sCD147 in patients with breast cancer. Furthermore, the biological and clinical significance of sCD147 in breast cancer has not been investigated.…”