Expression of cellular apoptosis susceptibility (CAS) in the human testis and testicular germ cell tumors.

Testicular germ cell tumors are the most frequent malignancies found in men between 15 and 44 years old. Although cellular apoptosis susceptibility (CAS) was demonstrated to be upregulated in breast cancer and colon cancer, the expression of CAS in the human testis and testicular germ cell tumors remained elusive. In the present study, CAS-positive signals were detected in the normal testicular tissues, cancer adjacent normal testicular tissues, seminoma, yolk sac tumor, and teratoma. Interestingly, the expression level of CAS in testicular germ cell tumors (TGCTs) (but not seminoma) was significantly lower than that of human testicular tissues and cancer adjacent normal testicular tissues, suggesting that decreased CAS contributed to the progression of TGCTs. Notably, the expression of CAS in seminoma was significantly higher than that of in the non-seminomas, consistent with the results from TCGA database. Furthermore, the localization of CAS is mainly restricted in the nucleus in the lesions of normal human testicular tissue and cancer adjacent normal testicular tissue. Although the expression of CAS was not significantly different between normal testicular tissue and seminoma, CAS was more enriched in cytoplasm in seminoma compared to the normal, cancer adjacent tissue and other types of TGCTs. The current results demonstrated reduced expression of CAS in the human testicular germ cell tumors and the CAS translocation from the nuclear to cytoplasm in seminoma, thereby supporting a possible role in normal testis function and in the development of seminoma.

Expression of CAS/CSE1L, the Cellular Apoptosis Susceptibility Protein, Correlates With Neoplastic Progression in Barrett's Esophagus.

BACKGROUND: Identifying the molecular switch responsible for the neoplastic progression of Barrett's esophagus (BE) and initiation of adenocarcinoma (ADC) is clinically essential and it will have a profound impact on patient diagnosis, prognosis, and treatment. The cellular apoptosis susceptibility gene CAS/CSE1L is overexpressed in various cancers, including a rare report on esophageal ADC; however, its expression in BE neoplasia has not been addressed. MATERIALS AND METHODS: We investigated the expression of the CAS/CSE1L protein immunohistochemically in 56 esophageal resection specimens for ADC arising in BE. For each specimen, a full representative section of the invasive ADC was selected to include, when possible, BE, low-grade dysplasia (LGD) and high-grade dysplasia (HGD). Samples were stained for CAS/CSE1L expression using a rabbit polyclonal antibody recognizing the N-terminus of human CAS/CSE1L. Protein expression levels were measured using the Allred semiquantitative scoring system. The data were evaluated using χ statistical analysis. Gene expression Omnibus was queried for CAS/CSE1L and BE neoplasia. RESULTS: We found minimal to absent CAS/CSE1L in all BE tissue samples; however, CAS/CSE1L was upregulated in 60% of LGD and overexpressed in HGD and ADC. The results were statistically significant (P<0.05). The localization of CAS/CSE1L protein was nuclear in BE; it became nuclear and cytoplasmic in LGD and HGD, and predominantly cytoplasmic in ADC. A similar progressive increase was observed for CAS/CSE1L gene expression. CONCLUSION: These findings show changes in CAS/CSE1L during BE progression. CAS/CSE1L may represent a potential marker for dysplasia/carcinoma.

Expression of cellular apoptosis susceptibility protein in serous ovarian carcinoma: a clinicopathologic and immunohistochemical study.

OBJECTIVE: This study investigated the expression of cellular apoptosis susceptibility protein (CAS) in serous ovarian carcinoma by immunohistochemistry and compared it with topoisomerase IIalpha (topo IIalpha), bcl-2, bcl-x, the frequency of apoptotic bodies (ABI), mitotic activity, and c-erbB-2 with regard to clinicopathologic variables. METHODS: Formalin-fixed, paraffin-embedded archival tissue sections of 10 benign serous cystadenomas, 10 serous neoplasms of low malignant potential (LMP), and 41 serous ovarian carcinomas were immunostained with antibodies to CAS, bcl-x, topo IIalpha, bcl-2, and c-erbB-2. Immunostaining for CAS, bcl-x, and bcl-2 was scored concerning approximate percentage of positive tumor cells and relative staining intensity. For c-erbB-2, at least 10% of tumor cells had to display membrane staining. Topo IIalpha-labeling indices were quantitated as the percentage of positively stained nuclei in 1000 tumor cells. ABIs were reported as the number of apoptotic bodies in 1000 tumor cells, mitotic activity as mitotic figures per 10 high power fields. RESULTS: CAS expression was negative in serous cystadenomas and LMP. In contrast, moderate or strong immunostaining was observed in 34 of 41 cases (83%) of serous carcinomas. CAS immunoreactivity was positively related with ABI (P = 0.0170), mitotic activity (P < 0.0001), c-erbB-2 (P = 0.0153), grade (P = 0.0107), and adverse outcome (P = 0.0035), but not with FIGO stage, topo IIalpha, bcl-2, and bcl-x. Other variables indicating outcome were topo IIalpha, c-erbB-2, and ABI. CONCLUSIONS: CAS is frequently upregulated in serous ovarian carcinomas, correlated with apoptosis and mitotic activity, and relevant prognostically. CAS protein expression may serve as a marker of aggressive tumor behavior in serous ovarian carcinomas.

Multiple genes in human 20q13 chromosomal region are involved in an advanced prostate cancer xenograft.

We analyzed a prostate cancer xenograft derived from a locally advanced tumor using combined cytogenetic, array-based comparative genomic hybridization and expression analyses. This analysis revealed that genes in the 20q13 chromosomal region, CSE1L, ZNF217, MYBL2, and STK15, were significantly overexpressed in this tumor. The expression pattern of these genes was then confirmed in two large human prostate cancer microarray databases. Furthermore, the MYBL2 and STK15 have been significantly overexpressed in prostate metastases, allowing a clear distinction between localized tumors and metastases. Our data suggest these genes to be involved in advanced stages of prostate tumorigenesis and as such, they may serve as markers for tumor progression.

Implication of the proliferation and apoptosis associated CSE1L/CAS gene for breast cancer development.

The CSEIL/CAS protein (CAS) is a Ran-binding protein with a function as a nuclear transport (export) factor. CSEIL/CAS, similar to Ran and other ran-binding proteins, plays at the same time an important role in the mitotic spindle checkpoint, which assures genomic stability during cell division. This checkpoint is frequently disturbed in neoplasms of various origin, including breast, hepatic and colonic tumors. CAS is located on chromosome 20ql3 and amplified in several cell lines, including breast, colon and bladder cancer. MEKl phosphorylation is known to be a reason for different CAS localization and activity. We evaluated the expression of CAS in 50 benign and malignant tumors of the breast by immunohistochemistry. Benign lesions of the breast (n=13) revealed a weak, predominantly cytoplasmatic CAS positivity. In ductal and lobular in situ carcinomas (n=17), 70-90% of the tumor cells were positive for anti-CAS staining which was predominantly cytoplasmatic. In invasive ductal and lobular carcinomas (n =20), 70-90% of the tumor cells stained positive with anti-CAS in a predominantly nuclear pattern. Different localization of CAS might affect its role not only for chromosome segregation, proliferation and apoptosis, but also its function in nuclear transport of proteins like retinoblastoma-gene-product, p53 and BRCAl. A different regulation in this checkpoint might contribute to the invasive potential in malignant carcinomas of the breast. Alteration of CAS-activity, possibly via MEKl-inhibition, might therefore be a possible option for breast cancer therapy.