Differential regulation of MAP kinase cascade in human colorectal tumorigenesis.

Hyper-activation of mitogen-activated protein kinase (MAPK) has recently been reported in several human cancers and activation of MAPK in those cancers may be associated with carcinogenesis through aberrant cell proliferation. To understand the roles of the MAPK pathway in colorectal tumorigenesis, we examined the status of extracellular signal-regulated protein kinases (ERK1/2) in 21 colorectal tumour specimens and compared it with that of paired normals. The specific MAPK activities were two- to tenfold lower in 71% (15 out of 21 cases) of colorectal tumours compared to those in paired normals. The individual MAPK kinase (MEK) correlated with MAPK activities (P = 0.006). Reduction of the MAPK and MEK activities in colorectal tumours was also observed in adenomas. These results suggested that down-regulation of the MAPK cascade may be caused by early genetic event(s) and that it may be related to the loss of normal growth control. Although MAPK activities were down-regulated both in adenomas and carcinomas, activities of the MAPKs in carcinomas were higher than those of paired adenomas. These results suggested that MAPK activities may be increased in the adenoma-to-carcinoma sequence and that it may play a role in the tumour progression. Observation of the differential regulation of MAPK activities in colorectal tumorigeneis suggested roles for the MAPK pathway in both positive and negative controls of cell growth.