Colorectal cancer (CRC) is the second most common cause of cancer-related death, encouraging the search for novel therapeutic targets affecting tumor cell proliferation and migration. These cellular processes are under tight control of two opposing groups of enzymes; kinases and phosphatases. Aberrant activity of kinases is observed in many forms of cancer and as phosphatases counteract such “oncogenic” kinases, it is generally assumed that phosphatases function as tumor suppressors. However, emerging evidence suggests that the lipid phosphatase SH2-domain-containing 5 inositol phosphatase (SHIP2), encoded by the INPPL1 gene, may act as an oncogene. Just like the well-known tumor suppressor gene Phosphatase and Tensin Homolog (PTEN) it hydrolyses phosphatidylinositol (3,4,5) triphosphate (PI(3,4,5)P3). However, unlike PTEN, the reaction product is PI(3,4)P2, which is required for full activation of the downstream protein kinase B (PKB/Akt), suggesting that SHIP2, in contrast to PTEN, could have a tumor initiating role through PKB activation. In this work, we investigated the role of SHIP2 in colorectal cancer. We found that SHIP2 and INPPL1 expression is increased in colorectal cancer tissue in comparison to adjacent normal tissue, and this is correlated with decreased patient survival. Moreover, SHIP2 is more active in colorectal cancer tissue, suggesting that SHIP2 can induce oncogenesis in colonic epithelial cells. Furthermore, in vitro experiments performed on colorectal cancer cell lines shows an oncogenic role for SHIP2, by enhancing chemoresistance, cell migration, and cell invasion. Together, these data indicate that SHIP2 expression contributes to the malignant potential of colorectal cancer, providing a possible target in the fight against this devastating disease.
The cancer/testis antigens (CTA) are a group of antigens expressed on germ cells of healthy testis and malignant tumors. We studied whether CTA are present on lentigo maligna (LM) and LM melanoma (LMM) samples. Immunohistochemical expression of a panel of CTA (MAGE-A1, A2- A3, NY-ESO-1, PRAME, SSX-2, and a MAGE-A antibody reactive with -A1, -A2, -A3, -A4, -A6, -A10, and -A12) was investigated in formalin-fixed paraffin-embedded samples from LMM (n = 20), LM (n = 8), chronically sun-exposed skin (n = 7), and healthy skin (n = 7). In 4 LMM lesions, the MAGE-A marker was positive. Another 3 LMM lesions were positive for MAGE-A1, MAGE-A2, and MAGE-A3. PRAME was positive in 18/20 LMM and 6/8 LM. We did not find expression of MAGE, NY-ESO-1, or SSX-2 in LM, thereby excluding these CTA as diagnostic markers to discern malignant melanocytes in LM from normal melanocytes. LMM did express MAGE, NY-ESO-1, and SSX-2. If a biopsy from a lesion suspect for LM shows positivity for MAGE, NY-ESO-1, and SSX-2, the lesion may actually be LMM. In contrast, PRAME expression was found in LM at low levels and in LMM at much higher levels, and absent in normal melanocytes. PRAME can potentially be used to discern normal melanocytes from malignant melanocytes.
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