EMMPRIN Promotes Angiogenesis, Proliferation, Invasion and Resistance to Sunitinib in Renal Cell Carcinoma, and Its Level Predicts Patient Outcome

Abstract

PurposeExtracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to play crucial roles, including in angiogenesis, in several carcinomas. However, the correlation between EMMPRIN levels and angiogenesis expression profile has not been reported, and the role of EMMPRIN in renal cell carcinoma (RCC) is unclear. In the present study, we evaluated the association of EMMPRIN with angiogenesis, its value in prognosis, and its roles in RCC.Experimental DesignEMMPRIN expression was examined in 50 RCC patients treated with radical nephrectomy. Angiogenesis, proliferation, and invasion activity were evaluated using EMMPRIN knockdown RCC cell lines. The size of EMMPRIN-overexpressing xenografts was measured and the degree of angiogenesis was quantified. EMMPRIN expression was evaluated in RCC patients who received sunitinib therapy and in sunitinib-resistant cells. Further, the relation between EMMPRIN expression and sensitivity to sunitinib was examined.ResultsEMMPRIN score was significantly associated with clinicopathological parameters in RCC patients, as well as being significantly correlated with microvessel area (MVA) in immature vessels and with prognosis. Down-regulation of EMMPRIN by siRNA led to decreased VEGF and bFGF expression, cell proliferation, and invasive potential. EMMPRIN over-expressing xenografts showed accelerated growth and MVA of immature vessels. EMMPRIN expression was significantly increased in patients who received sunitinib therapy as well as in sunitinib-resistant 786-O cells (786-suni). EMMPRIN-overexpressing RCC cells were resistant to sunitinib.ConclusionOur findings indicate that high expression of EMMPRIN in RCC plays important roles in tumor progression and sunitinib resistance. Therefore, EMMPRIN could be a novel target for the treatment of RCC.

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

“…Minardi et al [51] showed that VEGF expression was correlated with distant metastasis-free survival (DMFS) and OS in mRCC patients, but showed no association with regard to sunitinib treatment [51]. In a set of 50 Japanese RCC patients, Sato et al [52] investigated the Extracellular Matrix MetalloPRoteinase Inducer (EMMPRIN), a cell-surface glycoprotein that belongs to the immunoglobulin superfamily encoded by a gene localized to 19p13.3. High expression of EMMPRIN was seen for sunitinib-treated patients and sunitinib-resistant cells [52].…”

“…In a set of 50 Japanese RCC patients, Sato et al [52] investigated the Extracellular Matrix MetalloPRoteinase Inducer (EMMPRIN), a cell-surface glycoprotein that belongs to the immunoglobulin superfamily encoded by a gene localized to 19p13.3. High expression of EMMPRIN was seen for sunitinib-treated patients and sunitinib-resistant cells [52]. In the above-mentioned study of Motzer et al [33], baseline levels of angiopoietin-2 and matrix metalloproteinase were associated with tumor response, and HIF-1α expression was associated with PFS [33].…”

Recent Aspects of Sunitinib Therapy in Patients with Metastatic Clear-Cell Renal Cell Carcinoma: a Systematic Review of the Literature

“…Sato et al [9] investigated the role of EMMPRIN in resistance to sunitinib, showing in his study that the use of sunitinib may lead to EMMPRIN overexpression, a phenomenon related to tumor growth and angiogenesis activity.…”

“…Moreover, in most cases, this therapeutic option represents no definitive cure. Even in cases that initially respond well to sunitinib, tumor regrowth occurs owing to chemoresistance [9].…”

Overexpression of CD147 is associated with poor prognosis, tumor cell migration and ERK signaling pathway activation in hepatocellular carcinoma

“…Studies have focused on its potential biological functions in malignant tumors and have revealed that upregulation of CD147 may contribute to carcinogenesis and tumor cell migration in several cancer types, such as colorectal adenocarcinoma (10)(11)(12) and head and neck squamous cell carcinoma (13). Sato et al (14) further reported that CD147 expression levels are predictors of the outcome for renal cell carcinoma patients. A mechanistic assessment by Iacono et al (15) suggested that CD147 elevated the expression levels of various metalloproteinases to promote carcinogenesis, angiogenesis and metastasis (16).…”