Abstract
Colorectal cancer (CRC) is a heterogeneous disease that results from the accumulation of mutations in colonic mucosa cells. A subclass of CRC is characterized by microsatellite instability, which is thought to occur mainly through inactivation of the DNA mismatch repair genes MLH1 and MSH2. The inositol 5-phosphatase SHIP1 is expressed predominantly in hematopoietic cells. In this study, the expression of SHIP1 in carcinomas and its putative correlation with clinicopathologic parameters, expression of DNA repair genes and microsatellite instability was investigated. By analyzing a multi-tumor tissue microarray, expression of SHIP1 was detected in 48 out of 72 cancer entities analyzed. The expression of SHIP1 protein of 145 kDa was confirmed by Western blot analysis in 7 out of 14 carcinoma cell lines. Analysis of a large colorectal cancer tissue microarray with 1009 specimens revealed SHIP1 expression in 62% of the samples analyzed. SHIP1 expression was inversely correlated with lymph node metastasis, vascular invasion and tumor grade, and it was positively associated with left-sided tumor localization. Interestingly, a strong relationship between the expression of SHIP1 and nuclear and membranous beta-catenin and the DNA repair genes MLH1 and MSH2 was observed.
Highlights
Colorectal cancer (CRC) is the third most frequently occurring cancer in the western world [1].A small subgroup of CRCs exhibit inherited or somatic mutations in DNA mismatch repair genes, accompanied by microsatellite instability (MSI) [2]
To analyze the expression of the hematopoietic inositol 5-phosphatase SHIP1 in solid human cancers, we first performed Western blot analysis of carcinoma cell lines derived from breast cancer (MDA-MB-231, MDA-MB-468, MCF-7), colorectal cancer (SW-480, CaCo2, HT-29, HCT-116, HROC-24), liver cancer (Hep3B, HepG2, Huh7) and cholangio carcinoma (EGI-1, TFK-1, SKCHA-1)
SHIP1 has been shown to function as a tumor suppressor in acute myeloid leukemia due to the reduction of PI3K-AKT signaling [7,8,9,10,11,12,13]
Summary
Colorectal cancer (CRC) is the third most frequently occurring cancer in the western world [1]. A small subgroup (about 15%) of CRCs exhibit inherited or somatic mutations in DNA mismatch repair genes, accompanied by microsatellite instability (MSI) [2]. These cancers are generally different from microsatellite stable CRCs. These cancers are generally different from microsatellite stable CRCs They tend to arise in the proximal colon, display enhanced leukocyte infiltration, and their response to chemotherapy is different from that of microsatellite stable (MSS) CRCs [3]. SHIP2 knockdown in breast cancer cells results in reduced metastatic potential [5] Another inositol 5-phosphatase, synaptojanin 2, has been shown to be responsible for the metastatic potential of breast cancer cells [6]. SHIP1 in carcinomas, which shows endogenous expression only in the hematopoietic lineage and therein functions as a negative regulator of hematopoiesis and a suppressor of leukemogenesis [7,8,9,10,11,12,13]
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