Anomalous expression of the HLA-DR alpha and beta chains in ovarian and other cancers

Abstract

Tumor formation in immunocompetent hosts is believed to be dependent on the ability of tumor cells to evade the immune system, as suggested by the alterations of expression of the major histocompatibility complex (MHC) and related molecules in a number of cancers. Our previous serial analysis of gene expression (SAGE) study revealed that HLA-DRA (encoding the alpha chain of HLA-DR) is one of the most highly overexpressed genes in ovarian cancer. This finding was unanticipated, as overexpression of MHC molecules would be expected to increase tumor immunogenicity, therefore compromising tumor growth. We have now examined the expression of HLA-DR alpha chain in ovarian and a variety of other cancers using tissue arrays and found it overexpressed in a majority of the cancer tissues investigated. In contrast, the HLA-DR beta chain, which together with the alpha chain forms the functional HLA-DR complex, was not frequently found expressed in cancer, resulting to a lack of mature HLA-DR in these tissues. Interestingly, HLADRA and HLADRB transcripts were both found expressed in many other cancer types, including ovarian cancer, suggesting that the downregulation of HLADR beta chain is a post-transcriptional or post-translational mechanism. In addition, we observed high levels of the invariant chain (Ii/CD74) expression in both the cytoplasm and plasma membrane of ovarian tumor cells, possibly contributing to the lack of mature HLA-DR protein expression. Interestingly, we found that IFN-gamma could induce mature HLA-DR at the surface of normal ovarian cells, while this ability was reduced in tumor cells. Together, these data suggest that, while ovarian tumors overexpress HLA-DR alpha, perhaps as a result of inflammatory events in the tumor microenvironment, the tumor cells may have compensatory mechanisms to reduce the production of functional MHC class II molecules, thus reducing immunogenicity and favoring tumor growth. In addition, because of its ubiquitous expression in ovarian and other cancers, HLA-DR alpha may represent a novel biomarker for malignancy.

Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis

“…Since in parallel, high levels of CD74 expression in both the cytoplasm and plasma membrane of ovarian tumor cells were detected, it was argued that overexpression of the chaperone CD74 that is essential for HLA-DR trafficking and antigen loading may contribute to the observed lack of mature MHC molecules. [36][37][38] The same proposed pathomechanism may play a role in CML-BP as we detected up to 4.6-fold elevated CD74 protein levels in CD34 þ Ph þ BP blasts pointing to aberrant posttranslational processing of HLA polypeptides. This may explain the abnormal dendritic cell phenotypes in CML.…”

“…While coordinated expression and proper processing of these polypeptides are crucial for efficiency of professional antigen presenting cells, silencing or aberrant expression of MHC class I and class II molecules has been reported to be associated with high-grade malignancy and impairment of immunosurveillance. 35,36 Recently, elevated transcript levels of HLA-DRA, HLA-DRB but a lack of mature HLA-DR beta chains has been unexpectedly found in ovarian and other cancers. Since in parallel, high levels of CD74 expression in both the cytoplasm and plasma membrane of ovarian tumor cells were detected, it was argued that overexpression of the chaperone CD74 that is essential for HLA-DR trafficking and antigen loading may contribute to the observed lack of mature MHC molecules.…”

The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma

“…HSP90 is a chaperone protein that stabilizes several proteins that play crucial roles in oncogenic pathways, including SRC, ERBB2, EGFR, FLT3, Raf-1, AKT, HIF1a, and MET. 26 One of the HSP90 "client proteins" is the telomerase catalytic subunit, TERT. HSP90 associates with TERT and promotes its assembly into the active telomerase enzyme complex.…”

“…24,25 HSP90 plays a key role in the folding and function of TERT and more than 200 other oncogenic proteins including C-RAF, CDK4, AKT/PKB, mutant p53, and HIF-1a. [25][26][27] Depletion of functional HSP90 caused dramatic telomere shortening followed by apoptosis. 28,29 We hypothesized that HSP90 inhibition would potentiate the effect of telomerase inhibition therapy.…”

A conceptual and practical overview of cDNA microarray technology: implications for basic and clinical sciences

“…Further confirmation is also highly recommended at the protein level, such as by Western blot analysis, flow cytometry or immunohistochemistry. In this context, it is currently possible to evaluate genes at the protein level using tissue microarray assays (31)(32)(33). Tissue microarray assay is a method that allows the evaluation of up to one thousand tissues at once using a specific marker.…”