Abstract

Spatio-temporal cues defined for certain critical components in a particular developmental pathway provide a firm basis for detecting the order, hierarchy and “switching-off or on” of genes that regulate it. The various time-points at which genes are switched on/off determines the fate of what a cell does in terms of being functional or non-functional, due to disruption of that specific pathway. This piece of work reports a strong evidence, toward identifying such components (associated with Wnt-signaling) which indeed determine the transformation of a “blank-slate” (“cells of origin” and/or putative “cancer stem cells”) or “primitive-state” epithelial cells to an intermediate adenoma/polyp (dyspastic), and later to a proliferative (hyperplastic) or cancerous (neoplastic) state. The report discusses a critical temporal requirement of Caesin-Kinase I (CKI) and Human-Discs-large (hDlg), which have been identified as “early” and “late” acting molecules respectively, in a very crucial developmental event, that basically transforms “polyps” to full-fledged “carcinomas” (epithelial cancers) in COLORECTAL tumors. A concomitant loss of CKI protein, in cells mutant for APC, a tumor suppressor gene, basically initiates the process of early-late polyposis, which furthers the process of tumorigenesis, to finally give rise to confluent malignant cancers. The disturbance of architectural properties during metastasis, owing to the loss of apico-basal polarity of cells, consequently perturbs the hDlg protein expression, since it is basically a membrane associated protein, belonging to MAGUK (Membrane-Associated-Guanylate-Kinase) family. The loss of a critical cytoplasmic component of APC protein, which is lost in cells mutant for APC, actually governs the early loss of CKI during polyposis and consequently hDlg in later stages of colorectal carcinoma development. The detection of this very crucial parameter, served as a focal-point and a prominent diagnostic feature, for detection of effects, ie. gain/ loss of other components involved during progression of  CRC disease. The results presented here, prove that apart from being associated with each other as binding- partners during Wnt-signaling, the loss of CKI and APC, together, is indeed is responsible for triggering the normal epithelial cells of intestinal lining, to polyps followed by an awry late/confluent cancerous state, where hDlg expression gets aberrant. Coincidentally, the chromosomes on which these genes reside have been found to be dense and rich in SNPs (hot-spots), the details of which have been recently discussed in a separate report (Patidar & Bhojwani, 2013).

Keywords

APC, CKI, hDlg, spatio-temporal, Wnt-signaling, colorectal cancer.

Introduction