Ran, a Small GTPase Gene, Encodes Cytotoxic T Lymphocyte (CTL) Epitopes Capable of Inducing HLA-A33–restricted and Tumor-Reactive CTLs in Cancer Patients

Abstract

Purpose: The purpose is to identify a gene coding for tumor-associated antigen and peptide capable of inducing CTLs reactive to tumor cells with a HLA-A33-restricted fashion to provide scientific basis for specific immunotherapy to HLA-A33 ؉ cancer patients. Experimental Design: An expression gene-cloning method was used to identify the tumor-associated antigen gene. Northern blot analysis and immunohistochemistry were used to examine the mRNA and protein expression levels in various cells and tissues, respectively. Synthetic peptides were examined for their ability to induce HLA-A33؉ tumor-reactive CTLs in peripheral blood mononuclear cells from cancer patients.Result: A gene of small GTPase, Ran, which controls the cell cycle through the regulation of nucleocytoplasmic transport, mitotic spindle organization, and nuclear envelope formation, was found to encode epitopes recognized by the HLA-A33-restricted CTLs established from T cells infiltrating into gastric adenocarcinoma. The expression of the Ran gene was increased in most cancer cell lines and cancer tissues at both the mRNA and protein levels. However, it was not enhanced in the surrounding normal cells or tissues. It was also undetectable in normal tissues as far as tested. Ran-derived peptides at positions 48 -56 and 87-95 could induce CD8؉ peptide-specific CTLs reactive to tumor cells from HLA-A33؉ epithelial cancer patients in a HLA class I-restricted manner.Conclusions: Because of its increased expression in cancer cells and involvement in malignant transformation and/or the enhanced proliferation of cancer cells, the two Ran-directed peptides could be potent candidates in use for specific immunotherapy against HLA-A33 ؉ epithelial cancers.

Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer

“…[56][57][58][59][60][61][62] Aberrant nuclear localization of membrane receptors in cancer cells may be due to an increase in nuclear core complex activity, since nuclear core complex proteins such as Ran are often over-expressed in several types of cancer. 63,64 Consistent with this hypothesis, we noticed an over-expression of Ran protein in TOVs of all grades compared to LMPs. Ran is a small GTPbinding protein essential for the nucleocytoplasmic transport through the nuclear pore complex and is also involved in nuclear organization and cell cycle progression.…”

Characterization of a Novel Activated Ran GTPase Mutant and Its Ability to Induce Cellular Transformation

“…In particular, Ran has been suggested to serve as an indicator of the degree of tumor invasiveness in ovarian cancer, such that its high expression appears to be correlated with poor patient survival (11). Ran has also been reported to be overexpressed in colon, gastric, lung, and pancreatic tumor tissues, and the knockdown of Ran expression was shown to reduce the survival of different cancer cell lines (10,37).…”

Clinical Validation of Colorectal Cancer Biomarkers Identified from Bioinformatics Analysis of Public Expression Data

“…CKS2 is a subunit of cyclin dependent kinases and has been reported to be associated with liver metastasis of colon cancer (20,21). The expression of RAN, a small GTPase, has been shown to be increased in most types of cancer (22,23) while S100A11, a member of the S100 family shows either elevated or repressed expression levels depending on cancer types (24). ECT2, a Rho guanine nucleotide exchange factor, is a protooncogene cloned based on its transforming ability in fibroblast and is involved in cytokinesis (25,26).…”