Abstract
The most indecipherable component of solid cancer is the development of metastasis which accounts for more than 90% of cancer-related mortalities. A developmental program termed epithelial-mesenchymal transition (EMT) has also been shown to play a critical role in promoting metastasis in epithelium-derived solid tumors. By analyzing publicly available microarray datasets, we observed that ecotropic viral integration site 1 (EVI1) correlates negatively with SLUG, a master regulator of EMT. This correlation was found to be relevant as we demonstrated that EVI1 binds to SLUG promoter element directly through the distal set of zinc fingers and downregulates its expression. Many studies have shown that the primary role of SLUG during EMT and EMT-like processes is the regulation of cell motility in most of the cancer cells. Knockdown of EVI1 in metastatic colon cancer cell and subsequent passage through matrigel not only increased the invading capacity but also induced an EMT-like morphological feature of the cells, such as spindle-shaped appearance and led to a significant reduction in the expression of the epithelial marker, E-CADHERIN and increase in the expression of the mesenchymal marker, N-CADHERIN. The cells, when injected into immunocompromised mice, failed to show any metastatic foci in distant organs however the ones with EVI1, metastasized in the intraperitoneal layer and also showed multiple micro metastatic foci in the lungs and spleen. These findings suggest that in colon cancer EVI1 is dispensable for epithelial-mesenchymal transition, however, is required for metastasis.
Highlights
Ecotropicviral integration site 1 (EVI1), an oncogenic transcription factor, is known to be associated with adverse prognosis in several hematological malignancies and some solid cancers[1,2,3]
EVI1 inversely correlates with epithelial-mesenchymal transition (EMT) related markers in colon cancer patient samples Earlier we have shown that EVI1 delays cell cycle progression and inhibits cell proliferation in colon cancer cells in a p53-independent manner[11]
We checked six transcription factors (SLUG, SNAIL, TWIST 1/2, ZEB1/2), all of which are known to control the expression of E-CADHERIN in cancer cells[9]
Summary
Ecotropicviral integration site 1 (EVI1), an oncogenic transcription factor, is known to be associated with adverse prognosis in several hematological malignancies and some solid cancers[1,2,3]. The oncogenic potential of EVI1 was reflected by the transformation of Rat[1] fibroblasts where it shows anchorage-independent growth[4] as well as it was shown to be essential for cell proliferation and maintenance of embryonic/adult HSC and transformed leukemic cells[5]. EVI1 represses transforming growth factor (TGF) beta signaling pathway and plays a critical role in colon cancer tumor progression[6]. The role of EVI1 in colon cancer migration, invasion and metastasis are yet to be deciphered
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