Integrin A6 Cleavage in Mouse Skin Tumors

Abstract

Abstract:We have previously identified a structural variant of the 6 integrin (Laminin receptor) called 6p. The 6p variant is a 70 kDa form of the full-length 6 integrin (140 kDa) that remains paired with either the 1 or 4 subunit on the cell surface. 6p is produced by urokinase-type plasminogen activator (uPA), which removes the extracellular -barrel domain while the receptor is on the cell surface. The 6p integrin was present in human prostate cancer tissue but not in normal tissue and the cleavage of the 6 integrin extracellular domain promotes tumor cell invasion and migration on laminin. The objective of the present study was to determine whether the 6p integrin is observed in other models of carcinogenesis. Our results indicate detectable low levels of 6p in normal mouse skin, and comparatively elevated levels in mouse papillomas and squamous cell carcinomas induced by DMBA, TPA and MNNG treatments. Furthermore, we have found that 6p was present at high levels in skin melanomas of transgenic mice that over express activated Ha-ras under the control of the tyrosinase promoter. Finally, subcutaneous injection into athymic nude mice of a malignant mouse keratinocyte derived cell line (6M90) that is 6p negative, results in the development of tumors that contain 6p integrin. The latter results indicate that 6p is induced in vivo suggesting that the tumor microenvironment plays a major role in the production of 6p. Taken together, these data suggest that the cell surface cleavage of the 6 integrin may be a novel mechanism of integrin regulation and might be an important step during skin tissue remodeling and during carcinogenesis.

An novel role of sphingosine kinase-1 (SPHK1) in the invasion and metastasis of esophageal carcinoma

“…Between these cell lines, 124 genes were differentially expressed, including 71 upregulated genes and 53 downregulated genes in EC9706-P4 relative to EC9706 (cutoff, fold ≥ 2.0, Additional file 1 ). Most of the dysregulated genes have been previously shown to be involved in tumor invasion and metastasis, such as TFPI-2 [ 17 ], LOXL2 [ 22 - 24 ], ADAM12m [ 25 , 26 ], IGFBP1 [ 27 , 28 ], integrin α6 [ 29 , 30 ], CD44 [ 31 ]and CYR61 [ 32 ]. Expression of some of these genes were subsequently tested by QRT-PCR (Figure 1B ).…”