1434

CSE1L

CSE1 chromosome segregation 1-like (yeast);CSE1L;CSE1 chromosome segregation 1-like (yeast)

cellular apoptosis susceptibility protein|chromosome segregation 1-like protein|exp2|exportin-2|importin-alpha re-exporter

20q13

protein-coding

Colorectal cancer has high rates of recurrence and metastasis. Many patients with similar histopathological features show significantly different clinical outcomes, and these differences are primarily related to metastases undetected by current diagnostic methods. There is no useful serological marker for metastatic disease. We investigated the cellular apoptosis susceptibility (CSE1L/CAS) protein in comparison with carcinoembryonic antigen (CEA) as a marker for metastatic colorectal cancer. Using serum from 103 patients with stage I, II, III, and IV disease, CSE1L was detected in 36.0% (9 of 25), 57.7% (15 of 26), 71.4% (30 of 42), and 88.9% (8 of 9) of patients, respectively; a pathological CEA level was found in 16.0% (4 of 25), 42.3% (11 of 26), 47.6% (20 of 42), and 77.8% (7 of 9) of patients, respectively; a combined CSE1L/CEA assay was detected in 48.0% (12 of 25), 65.4% (17 of 26), 88.1% (37 of 42), and 100% (9 of 9) of patients, respectively. Lymphatic metastasis is an important predictor of poor prognosis and crucial for determination of therapeutic strategy. Serum CSE1L was detected in 74.5% (38 of 51) of patients with lymph node metastasis, whereas a pathological CEA level was found in only 52.9% (27 of 51) of the same patients (P < 0.001); the combined CSE1L/CEA assay increased sensitivity to 90.2% (46 of 51). Animal experiments showed CSE1L reduction in B16-F10 melanoma cells correlated with decreased metastasis to the colorectal tract in C57BL/6 mice. These results indicate that assay of serum CSE1L may facilitate diagnosis of colorectal cancer lymphatic metastases; furthermore, CSE1L is a possible therapeutic target.

BACKGROUND: Ras plays an important role in colorectal cancer progression. CSE1L (chromosome segregation 1-like) gene maps to 20q13, a chromosomal region that correlates with colorectal cancer development. We investigated the association of CSE1L with Ras in colorectal cancer progression. METHODS: The effect of CSE1L on metastasis-stimulating activity of Ras was studied in an animal model with tumor cells expressing CSE1L-specific shRNA and v-H-Ras. CSE1L expression was evaluated by the immunohistochemical analysis of 127 surgically resected colorectal tumors. K-Ras mutations were analyzed by direct sequencing. RESULTS: CSE1L knockdown reduced Ras-induced metastasis of B16F10 melanoma cells in C57BL/6 mice. v-H-Ras expression altered the cellular trafficking of CSE1L and increased CSE1L secretion. Most colorectal tumors were positive for CSE1L staining (98.4%, 125 of 127). Colorectal tumors with K-Ras mutation or high cytoplasmic CSE1L expression were correlated with T status (depth of tumor penetration; P = .004), stage (P = .004), and lymph node metastasis (P = .019). CONCLUSIONS: CSE1L may be a target for treating Ras-associated tumors. Analysis of K-Ras mutation and CSE1L expression may provide valuable clinical and pathological information to aid in the determination of treatment options for colorectal cancer.

BACKGROUND: Ras plays an important role in colorectal cancer progression. CSE1L (chromosome segregation 1-like) gene maps to 20q13, a chromosomal region that correlates with colorectal cancer development. We investigated the association of CSE1L with Ras in colorectal cancer progression. METHODS: The effect of CSE1L on metastasis-stimulating activity of Ras was studied in an animal model with tumor cells expressing CSE1L-specific shRNA and v-H-Ras. CSE1L expression was evaluated by the immunohistochemical analysis of 127 surgically resected colorectal tumors. K-Ras mutations were analyzed by direct sequencing. RESULTS: CSE1L knockdown reduced Ras-induced metastasis of B16F10 melanoma cells in C57BL/6 mice. v-H-Ras expression altered the cellular trafficking of CSE1L and increased CSE1L secretion. Most colorectal tumors were positive for CSE1L staining (98.4%, 125 of 127). Colorectal tumors with K-Ras mutation or high cytoplasmic CSE1L expression were correlated with T status (depth of tumor penetration; P = .004), stage (P = .004), and lymph node metastasis (P = .019). CONCLUSIONS: CSE1L may be a target for treating Ras-associated tumors. Analysis of K-Ras mutation and CSE1L expression may provide valuable clinical and pathological information to aid in the determination of treatment options for colorectal cancer.

tumor-derived microvesicles are rich in metastasis-related proteases and play a role in the interactions between tumor cells and tumor microenvironment in tumor metastasis. Because shed microvesicles may remain in the extracellular environment around tumor cells, the microvesicle membrane protein may be the potential target for cancer therapy. Here we report that chromosome segregation 1-like (CSE1L) protein is a microvesicle membrane protein and is a potential target for cancer therapy. v-H-Ras expression induced extracellular signal-regulated kinase (ERK)-dependent CSE1L phosphorylation and microvesicle biogenesis in various cancer cells. CSE1L overexpression also triggered microvesicle generation, and CSE1L knockdown diminished v-H-Ras-induced microvesicle generation, matrix metalloproteinase (MMP)-2 and MMP-9 secretion and metastasis of B16F10 melanoma cells. CSE1L was preferentially accumulated in microvesicles and was located in the microvesicle membrane. Furthermore, anti-CSE1L antibody-conjugated quantum dots could target tumors in animal models. Our findings highlight a novel role of Ras-ERK signaling in tumor progression and suggest that CSE1L may be involved in the "early" and "late" metastasis of tumor cells in tumorigenesis. Furthermore, the novel microvesicle membrane protein, CSE1L, may have clinical utility in cancer diagnosis and targeted cancer therapy.