Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor

Abstract

Abstract. Recently, we identified htid-1, the human counterpart of the Drosophila tumor suppressor gene lethal(2)tumorous imaginal discs [l(2)tid], as a direct molecular ligand of the adenomatous polyposis coli (APC) tumor suppressor. The gene encodes three cytosolic (Tid50, Tid48 and Tid46) and three mitochondrial (Tid43, Tid40 and Tid38) proteins. In the colorectal epithelium the cytosolic forms hTid50/hTid48 interact under physiological conditions with the N-terminal region of APC. This complex which associates with additional proteins such as Hsp70, Hsc70, Actin, Dvl and Axin defines a novel physiological state of APC unrelated to ß-catenin degradation. Here we show that the expression of the genes htid-1 and APC was altered in colorectal tumors. These changes concerned both the localization and the expression level of all three htid-1 splice variants and of APC. Furthermore, we showed that the protein products of the two tumor suppressors co-localized in the basal and apical region of normal colon epithelia and that loss of differentiation capacity of colorectal cancers correlated with a shift in their expression patterns from compartmentalized to diffuse cytoplasmic. These findings support our hypothesis that the building of the multi-component complex mentioned above is associated with the maintenance of the polarity of cells and tissues. In addition, we provide evidence that colon cancer progression correlates with up-regulation of htid-1 and its ligand Hsp70. Since the Tid proteins are members of the DnaJ-like protein family, an essential component of the Hsp70/Hsc70 chaperone machinery, our findings describe a novel, causal link between the function of chaperone machines, APC-mediated Wg/Wnt signaling and tumor development.

Tid1, the Mammalian Homologue of Drosophila Tumor Suppressor Tid56, Mediates Macroautophagy by Interacting with Beclin1-containing Autophagy Protein Complex

“…In the case of Tid1, aberrant expression of Tid1 has been found in some types of human cancer. In lung cancer, Tid1 is expressed at lower levels than normal counterpart cells, whereas Tid1 is overexpressed in colon cancer (12,43). In mouse models, overexpression of Tid1 suppresses growth of human head and neck cancer cells and melanoma cells (7,19).…”

Multi-faceted role of HSP40 in cancer

“…However, recently Kurzik-Dumke et al [56] reported the existence of a multi-protein complex of human Tid1/ APC/HSP70/Hsc70/Axin/Dvl. The same study also found that overexpression and loss of polarization of hTid1 is correlated with progression of colon cancer [56]. These observations imply that HSP70/ Hsc70 may be partners of Tid1 function in some of the cancers.…”

“…Recent studies point out that progression of colorectal cancer correlates with overexpression and loss of polarization of the expression of hTid-1. This study demonstrated that Tid1 functions as a ligand of APC (adenomatous polyposis coli), a tumor suppressor, supporting its role in Wnt signaling [56].…”

“…Tid1 (DNAJA3) has been studied in skin cancer [55], colon cancer [56] and in gliomas [47]. Tid1 has two alternatively spliced isoforms, hTid-1(L) and hTid-1(S).…”

Instructive reconstruction: A new role for apoptosis in pattern formation

“…There are also indications of a conserved Wnt-HSP link across metazoans. For instance, in the human colon cancer cell lines (primarily HT-29 cells) Hsc70 and Hsp70 proteins have been identified as binding to the axin-APC complex which is known to degrade b-catenin, the cellular mediator of Wnt signalling [24,25]. New evidence continues to emerge of the importance of HSPs for development, many of which could be mediated through Wnt-HSP interactions.…”