CSE1L Links cAMP/PKA and Ras/ERK pathways and regulates the expressions and phosphorylations of ERK1/2, CREB, and MITF in melanoma cells.

The Ras/ERK (extracellular signal-regulated protein kinase) and cAMP/PKA (protein kinase A) pathways are essential for the transcriptional activities of CREB (cAMP response element binding protein) and MITF (microphthalmia-associated transcription factor) in melanogenesis and the progression of melanoma. However, the interaction between Ras/ERK and cAMP/PKA pathways in the melanogenesis and progression of melanoma is not fully known. Here, we report that CSE1L (chromosome segregation 1-like protein) regulates cAMP/PKA-induced CREB and MITF expressions as well as Ras-induced ERK1/2 phosphorylation. IBMX, a cAMP/PKA activator, treatment induced CSE1L phosphorylation and augmented Ras-induced ERK1/2 phosphorylation. CSE1L knockdown by CSE1L shRNA expression vectors inhibited Ras-induced ERK1/2 phosphorylation and melanogenesis in melanoma cells. CSE1L overexpression increased phospho-CREB expression; CSE1L knockdown also inhibited Ras-induced phospho-CREB, MITF, and tyrosinase expressions, regardless of the presence of IBMX. This study identifies CSE1L links and controls the Ras/ERK and cAMP/PKA pathways in the melanogenesis of melanoma cells. Melanomas frequently develop drug resistance via paradoxical activation of Ras/Raf/MEK/ERK or alternatively activated Ras/ERK and cAMP/PKA pathways. Thus CSE1L may be a potential target for treating melanomas that harbor Ras mutations or are resistant to drugs targeting Raf/MEK/ERK. © 2015 Wiley Periodicals, Inc.

CAS (CSE1L) signaling pathway in tumor progression and its potential as a biomarker and target for targeted therapy.

CSE1L (chromosome segregation 1-like protein), also named as CAS (cellular apoptosis susceptibility protein), is highly expressed in most cancer types. CSE1L/CAS is a multiple functional protein that plays roles in apoptosis, cell survival, chromosome assembly, nucleocytoplasmic transport, microvesicle formation, and cancer metastasis; some of the functions are explicitly correlated. CSE1L is also a cancer serum biomarker. The phosphorylation of CAS is regulated by the extracellular signal-regulated kinase (ERK). The RAS/RAF/MAPK/ERK signaling pathways are the essential targets of most targeted cancer drugs, thus serum phosphorylated CSE1L may be a potential biomarker for monitoring drug resistance in targeted therapy. CSE1L can regulate Ras-induced ERK phosphorylation. CSE1L also regulates the expression and phosphorylation of CREB (cAMP response element binding protein) and MITF (microphthalmia-associated transcription factor) and is thus involved in the melanogenesis and progression of melanoma. CAS is an exosome/microvesicle membrane protein. Tumor cells consistently secrete microvesicles and tumor-derived microvesicles may be accumulated around tumors. Therefore, microvesicle membrane CSE1L may be a potential target for the development of high-efficacy antibody-drug conjugates (ADCs) for cancer therapy. This review will focus on CSE1L expression in cancers, its relationship to Ras/ERK and cAMP/PKA signaling pathways in melanoma development, its potential for the development of ADCs and tumor imaging reagents, and secretory phosphorylated CSE1L for monitoring the emergence of drug resistance in targeted cancer therapy.

Early decline in serum phospho-CSE1L levels in vemurafenib/sunitinib-treated melanoma and sorafenib/lapatinib-treated colorectal tumor xenografts.

BACKGROUND: Although targeted therapies have improved the clinical outcomes of cancer treatment, tumors resistance to targeted drug are often detected too late and cause mortality. CSE1L is secreted from tumor and its phosphorylation is regulated by ERK1/2. ERK1/2 is located downstream of various growth factor receptors and kinases, the targets of most targeted drugs. Serum phospho-CSE1L may be a marker for monitoring the efficacy of targeted therapy. METHODS: We used mice tumor xenograft model to study the assay of serum phosphorylated CSE1L for early detecting the efficacy of targeted drugs. The phosphorylation status of CSE1L in vemurafenib and sorafenib treated tumor cells were assayed by immunoblotting with antibody against phosphorylated CSE1L. RESULTS: Ras activation increased phospho-CSE1L expression in B16F10 melanoma cells. Vemurafenib and sorafenib treatment did not significantly reduce the total CSE1L levels; however, they inhibited ERK1/2 and CSE1L phosphorylation in A375 melanoma cells and HT-29 colorectal cancer cells. In the melanoma xenograft model, serum phospho-CSE1L level declined 5 days after vemurafenib/sunitinib treatment and 3 days after sorafenib/lapatinib treatment in the HT-29 colon cancer xenograft model. Vemurafenib/sunitinib and sorafenib/lapatinib treatments resulted in tumor regression. CONCLUSIONS: Our results indicated that serum phospho-CSE1L is useful for early detecting the efficacy of targeted therapy in initial treatment and for monitoring emerging secondary drug resistance to facilitate timely therapeutic decision making.

Inverse correlation of phospho-KDR/Flk-1 expression and stage of colorectal cancer: implication of the significance of neoangiogenesis in activated VEGFR-2 expressing early stage colorectal adenocarcinomas.

The activation of vascular endothelial cell growth factor receptors (VEGFRs) plays an essential role in cancer progression. In this study, we investigated the expression of phosphorylated VEGFR-2 (or phospho-KDR/Flk-1), the activated form of VEGFR-2, in human colorectal adenomas and colorectal adenocarcinomas. Phospho-KDR/Flk-1 showed weak expression in the normal colorectal tissue. Phospho-KDR/Flk-1 was mainly stained in the cytoplasm of colorectal adenomas, and was stained in both the cytoplasm and nuclei colorectal adenocarcinomas. There was no indication of increased phospho-KDR/Flk-1 expression in the colorectal adenocarcinomas, as compared to that of colorectal adenomas. Furthermore, there was an inverse relationship of phospho-KDR/Flk-1 expression with cancer stage (p < 0.0001), lymph node metastasis (p = 0.011), and distant metastasis (p = 0.021) of the colorectal adenocarcinomas. Our results indicate that early stage colorectal adenocarcinomas with highly activated (phosphorylated) VEGFR-2 expression may indicate the significance of neoangiogenesis of the tumors.

Correlations between cytoplasmic CSE1L in neoplastic colorectal glands and depth of tumor penetration and cancer stage.

BACKGROUND: Colorectal carcinomas spread easily to nearby tissues around the colon or rectum, and display strong potential for invasion and metastasis. CSE1L, the chromosome segregation 1-like protein, is implicated in cancer progression and is located in both the cytoplasm and nuclei of tumor cells. We investigated the prognostic significance of cytoplasmic vs. nuclear CSE1L expression in colorectal cancer. METHODS: The invasion- and metastasis-stimulating activities of CSE1L were studied by in vitro invasion and animal experiments. CSE1L expression in colorectal cancer was assayed by immunohistochemistry, with tissue microarray consisting of 128 surgically resected specimens; and scored using a semiquantitative method. The correlations between CSE1L expression and clinicopathological parameters were analyzed. RESULTS: CSE1L overexpression was associated with increased invasiveness and metastasis of cancer cells. Non-neoplastic colorectal glands showed minimal CSE1L staining, whereas most colorectal carcinomas (99.2%, 127/128) were significantly positive for CSE1L staining. Cytoplasmic CSE1L was associated with cancer stage (P=0.003) and depth of tumor penetration (P=0.007). Cytoplasmic CSE1L expression also correlated with lymph node metastasis of the disease in Cox regression analysis CONCLUSIONS: CSE1L regulates the invasiveness and metastasis of cancer cells, and immunohistochemical analysis of cytoplasmic CSE1L in colorectal tumors may provide a useful aid to prognosis.

High nuclear expression of phosphorylated extracellular signal-regulated kinase in tumor cells in colorectal glands is associated with poor outcome in colorectal cancer.

Extracellular signal-regulated kinase (ERK) is a major downstream transducer of Ras and plays an important role in transducing extracellular signals to the nuclei of cells. It is located in both the cytoplasm and the nucleus of cells. The nuclear localization of phosphorylated or activated ERK is involved in the invasive behavior of tumor cells. We studied the association between Ras mutation/ERK activation and the prognosis of patients with colorectal cancer. We analyzed 126 surgically resected colorectal cancer specimens for K-Ras mutation using direct sequencing. Activation/phosphorylation of ERK was assayed by immunohistochemistry with tissue microarray, and the staining intensity was analyzed using a semiquantitative scoring system. K-Ras mutations were detected in 32.5% (41/126) of the colorectal tumors. Colorectal glands are important functional organs in colorectal tissue and form the origin of colorectal carcinomas. Tissue microarray immunohistochemistry tests showed that tumors in colorectal cancer specimens were significantly stained for phospho-ERK (100%; 126/126), whereas nonneoplastic colorectal glands mainly showed faint phosphorylated ERK staining. High nuclear phospho-ERK expression in tumors was associated with highly invasive cancer stage and T status of the disease. Kaplan-Meier analysis showed that nuclear but not cytoplasmic phosphorylated ERK expression correlated with the patients' overall survival rate (P = .039). Colorectal adenomas including tubular adenomas and tubulovillous adenomas mainly showed weak cytoplasmic phospho-ERK expression. Our results suggest that immunohistologic analysis of phosphorylated ERK expression in colorectal glands may aid the diagnosis of colorectal cancer and that nuclear phosphorylated ERK might be a valuable prognostic marker for colorectal cancer.

High nuclear phosphorylated extracellular signal-regulated kinase expression associated with poor differentiation, larger tumor size, and an advanced stage of breast cancer.

Extracellular signal-regulated kinase (ERK1/2) is implicated in the malignant behavior of breast cancer cells. However, previous clinical-pathological studies have shown that expression of activated/phosphorylated ERK1/2 is not associated with enhanced proliferation and invasion of mammary carcinomas. ERK1/2 is expressed in the cytoplasm, and activated/phosphorylated ERK1/2 translocates to the nucleus. The aim of this study is to evaluate nuclear phosphorylated ERK1/2 as a biomarker for breast cancer prognosis. The clinical-pathological relation of cytoplasmic/nuclear phosphorylated ERK1/2 was analyzed in 105 surgically resected breast cancer specimens by immunohistochemistry with tissue microarray. The results showed that non-neoplastic breast tissue mainly showed faint phosphorylated ERK1/2 staining. No statistically significant association was found between the level of cytoplasmic phosphorylated ERK1/2 expression and the clinical features of the disease. High nuclear phosphorylated ERK1/2 expression was associated with high grade (poor differentiation, p = = 0.010), high T status (larger tumor size, p = 0.033), and an advanced stage (p = 0.018) of the disease. Thus, nuclear phosphorylated ERK1/2 is associated with enhanced proliferation and invasion of mammary carcinomas and may be a biomarker for breast cancer prognosis and the determination of therapeutic strategies.

CSE1L, a novel microvesicle membrane protein, mediates Ras-triggered microvesicle generation and metastasis of tumor cells.

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.

The prognostic significance of nuclear CSE1L in urinary bladder urothelial carcinomas.

Prognosis of urinary bladder urothelial carcinomas may be challenging; many tumors with similar histopathologic features show significantly different clinical outcomes. CSE1L, the chromosome segregation 1-like protein, is both a cytoplasmic and nuclear protein. We investigated the cytoplasmic/nuclear expression pattern of CSE1L to determine its potential prognostic significance. In immunohistochemical analysis, nonneoplastic urothelium showed faint CSE1L staining, whereas all tumors in the bladder cancer specimens had significant staining for CSE1L (100%, or 38/38). CSE1L cytoplasmic/nuclear staining was defined based on relative staining intensity. A total of 20 (52.6%) of 38 cancer specimens had strong nuclear CSE1L staining, and 44.7.3% (17/38) of the samples had strong cytoplasmic CSE1L staining. Bladder urothelial carcinomas with high CSE1L nuclear staining had a significantly lower overall survival rate (log-rank test, P = .011). CSE1L expression was not correlated with tumor stage, likely reflecting the faultiness of current urothelial carcinoma evaluation methods. Our results suggest that nuclear CSE1L may play an oncogenic role in bladder tumor progression and that immunohistochemical staining of nuclear CSE1L may be useful for the prognosis of bladder urothelial carcinomas.

Clinical-pathological correlation of K-Ras mutation and ERK phosphorylation in colorectal cancer.

The Ras-ERK pathway is frequently up-regulated in colorectal cancer. We analyzed the clinical-pathological correlation of K-Ras mutation and phospho-ERK expression in colorectal cancer. K-Ras mutations were detected in only 32.5% (41/126) of the colorectal cancer cases, while all cancers were positive for phospho-ERK staining. Colorectal cancer with wild-typeK-Ras and low phospho-ERK expression had a significantly higher survival rate (log-rank P = 0.04). There were 9 cases of K-Ras mutation/low phospho-ERK diseases; 88.9% (8/9) of them were stage III/IV diseases. High phospho-ERK expression was associated with a high stage and T status of the cancer, yet combined K-Ras mutation/phospho-ERK expression analysis further increased the efficiency of colorectal cancer prognosis. Our results demonstrate that Ras-ERK pathway correlated closely with colorectal cancer progression. Moreover, although colorectal cancer with K-Ras mutations has a more aggressive phenotype; the mutation rate is not very high. Phospho-ERK may be a useful marker in combination with K-Ras for improving the prognosis of colorectal cancer.

Serum cellular apoptosis susceptibility protein is a potential prognostic marker for metastatic colorectal cancer.

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.

Increased cellular apoptosis susceptibility (CSE1L/CAS) protein expression promotes protrusion extension and enhances migration of MCF-7 breast cancer cells.

Microtubules are part of cell structures that play a role in regulating the migration of cancer cells. The cellular apoptosis susceptibility (CSE1L/CAS) protein is a microtubule-associated protein that is highly expressed in cancer. We report here that CSE1L regulates the association of α-tubulin with ß-tubulin and promotes the migration of MCF-7 breast cancer cells. CSE1L was associated with α-tubulin and ß-tubulin in GST (glutathione S-transferase) pull-down and immunoprecipitation assays. CSE1L-GFP (green fluorescence protein) fusion protein experiments showed that the N-terminal of CSE1L interacted with microtubules. Increased CSE1L expression resulted in decreased tyrosine phosphorylation of α-tubulin and ß-tubulin, increased α-tubulin and ß-tubulin association, and enhanced assembly of microtubules. Cell protrusions or pseudopodia are temporary extensions of the plasma membrane and are implicated in cancer cell migration and invasion. Increased CSE1L expression increased the extension of MCF-7 cell protrusions. In vitro migration assay showed that enhanced CSE1L expression increased the migration of MCF-7 cells. Our results indicate that CSE1L plays a role in regulating the extension of cell protrusions and promotes the migration of cancer cells.

Presence of secretory cellular apoptosis susceptibility protein in cerebrospinal fluids of patients with intracerebral hemorrhage caused by stroke and neurotrauma.

OBJECTIVE: The blood-brain barrier (BBB) is a specialized structure that separates blood vessels from the central nervous system (CNS) and restricts the entry of biomolecules and cells into the brain. Matrix metalloproteinase-2 (MMP-2) produced by interferon-gamma-activated microglia (brain macrophages) is essential for disrupting the glia limitans of BBB, which is critical for lymphocytes penetration into brain capillaries in various CNS disorders. The cellular apoptosis susceptibility (CSE1L/CAS) protein has been shown to regulate MMP-2 secretion. METHODS: We examined if CSE1L played a role in regulating the progression of intracerebral brain hemorrhage disorders. RESULTS: CSE1L was detected by immunoblotting in cerebrospinal fluids (CSFs) of patients with intracerebral hemorrhage brain disorders, including stroke and neurotrauma. Interferon-gamma treatment induced CSE1L expression and increased the secretions of CSE1L and MMP-2 by U937 macrophages. Moreover, tranfection of U937 macrophages with siRNA that targeted CSE1L inhibited interferon-gamma-induced CSE1L and MMP-2 secretion by U937 macrophages. The numbers of lymphocytes in CSF were correlated with the levels of CSE1L and MMP-2 in patients' CSF. CONCLUSIONS: Our results suggest that CSE1L plays a role in regulating MMP-2-mediated BBB breakdown and it may be a target for control of BBB permeability in intracerebral brain hemorrhage disorders.

Higher prevalence of secretory CSE1L/CAS in sera of patients with metastatic cancer.

Metastatic markers are highly useful diagnostic and prognostic indicators of cancer metastasis. Herein, we report that secretory CSE1L/CAS, a cellular apoptosis susceptibility protein, is a new marker for metastatic cancer. CAS was colocalized with matrix metalloproteinase-2 in vesicles surrounding the outside of MCF-7 cell membranes, and the COOH-terminal domain of CAS was associated with matrix metalloproteinase-2-containing vesicles. Immunohistochemical staining for CAS was positive in the stroma and gland lumens of human metastatic cancer tissues. CAS was also detected in conditioned medium from B16-F10 melanoma cells and more frequently in the sera of patients with metastatic cancer than in sera from patients with primary cancer. Specifically, the prevalence of serum CAS in serum samples from 146 patients was 58.2% (32 of 55), 32.0% (8 of 25), and 12.1% (8 of 66) for patients with metastatic, invasive, and primary cancers, respectively. Our results suggest that CAS is a secretory protein associated with cancer metastasis, which may have clinical utility in metastatic cancer screening and diagnosis.

Function of CSE1L/CAS in the secretion of HT-29 human colorectal cells and its expression in human colon.

The secretion of colorectal epithelium is important for maintaining the physiological function of colorectal organ. Herein, we report that cellular apoptosis susceptibility (CAS) (or CSE1L) protein regulates the secretion of HT-29 human colorectal cells. Polarity is essential for directed secretion of substances produced by epithelial cells to the external (luminal) compartment; CAS overexpression induced polarization of HT-29 cells. CAS was punctate stained in the cytoplasm of HT-29 cells, and CAS overexpression increased the translocation of CAS-stained vesicles to the cytoplasm near cell membrane and cell protrusions. CAS overexpression increased the secretion of carcinoembryonic antigen (CEA) and cathepsin D. Immunohistochemistry showed CAS was positively stained in the goblet cells of colon mucosa and cells in the crypts of Lieberkühn of human colon as well as the glands in metastatic colorectal cancer tissue. Our results suggest that CAS regulates the secretion of colorectal cells and may regulate the metastasis of colorectal cancer.

CAS Enhances Chemotherapeutic Drug-Induced p53 Accumulation and Apoptosis: Use of CAS for High-Sensitivity Anticancer Drug Screening.

ABSTRACT Cells attacked by cytotoxic toxins may express apoptosis-related proteins such as p53 to kill themselves, so as not to affect surrounding healthy cells. These apoptosis-related proteins are also crucial for inducing apoptosis of tumor cells in cancer chemotherapy. CSE1L/CAS is a cellular apoptosis susceptibility protein that plays important roles in mediating cell apoptosis induced by various cytotoxic toxins and chemotherapeutic drugs. Our studies showed that CAS over-expression increased p53 accumulation and apoptosis induced by 5-fluorouracil, doxorubicin, cisplatin, and tamoxifen in HT-29 cancer cells. A method based on coexpression of CAS with green fluorescence protein (GFP) was developed for high-sensitivity anticancer drug screening. Cancer cells transfected with CAS- and GFP-expressing vectors or the control and GFP-expressing vectors were grown on 96-well microplates, treated with compounds to be screened, and detected with a microplate fluorescence reader. GFP fluorescence decreased following cancer cell death induced by the anticancer compounds. CAS transfection enhanced the cytotoxicities of anticancer compounds and therefore increased the decline in GFP fluorescence. Thus, anticancer compounds could be identified more sensitively. Our study indicates that CAS is an important p53 and apoptosis regulator and may be used for high-throughput anticancer drug screening as well as cytotoxic toxin assays.

A modified mutation detection method for large-scale cloning of the possible single nucleotide polymorphism sequences.

Although the human genome has been nearly completely sequenced, the functions and the roles of the vast majority of the genes, and the influences of single nucleotide polymorphisms (SNPs) in these genes are not entirely known. A modified mutation detection method was developed for large-scale cloning of the possible SNPs between tumor and normal cells for facilitating the identification of genetic factors that associated with cancer formation and progression. The method involves hybridization of restriction enzyme-cut chromosomal DNA, cleavage and modification of the sites of differences by enzymes, and differential cloning of sequence variations with a designed vector. Experimental validations of the presence and location of sequence variations in the isolated clones by PCR and DNA sequencing support the capability of this method in identifying sequence differences between tumor cells and normal cells.

High expression of cytoplasmic phosphorylated CSE1L in malignant melanoma but not in benign nevi: phosphorylated CSE1L for the discrimination between melanoma and benign nevi.

Melanoma is difficult to treat when it has metastasized. Discrimination between melanoma and benign nevi in melanocytic lesions is crucial for identifying melanomas and consequently improving melanoma treatment and prognosis. The chromosome segregation 1-like (CSE1L) protein has been implicated in cancer progression and is regulated by phosphorylation by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, a critical pathway in melanoma progression. We studied phosphorylated CSE1L expression in human melanoma and benign nevi specimens. Immunohistochemistry with tissue microarray using antibody against phosphorylated CSE1L showed that melanomas exhibited considerable staining for phosphorylated CSE1L (100%, 34/34), whereas the benign nevi showed only faint staining (0%, 0/34). Melanomas mainly exhibited cytoplasmic phospho-CSE1L distribution, whereas the benign nevi mainly exhibited nuclear phospho-CSE1L distribution. Moreover, immunohistochemistry with anti-CSE1L antibody revealed that CSE1L mainly exhibited cytoplasmic/nuclear distribution and nuclear distribution was the dominant. Immunofluorescence with B16F10 melanoma cells showed cytoplasmic distribution of phospho-CSE1L and nuclear distribution of CSE1L. Our results indicated that nuclear CSE1L is mainly non-phosphorylated CSE1L and is involved in gene regulation and cytoplasmic CSE1L is mainly phosphorylated CSE1L and is involved in cytoplasmic signaling regulation in melanocytic tumorigenesis. Furthermore, immunohistochemical analysis of cytoplasmic phospho-CSE1L may aid in the diagnosis of melanoma.

CSE1L modulates Ras-induced cancer cell invasion: correlation of K-Ras mutation and CSE1L expression in colorectal cancer progression.

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.