Abstract
Tumor metastasis, the major problem for clinical oncology in colon cancer treatment, is linked with an epithelial-mesenchymal transition (EMT). The observed cellular transformation in this process is manifested by cell elongation, enhanced cell migration and invasion ability, coordinated by cytoskeleton reorganization. In the present study, we examined the role of tubulin-β4 (TUBB4B) downregulation that occurs during EMT in colon cancer cells, in the modulation of the function of microtubules. Based on biochemical and behavioral analysis (transmigration) we posit that the decrease of the TUBB4B level is critical for microtubule-vimentin interaction and contributes to the maintenance of polarity in migrating cells. The microscopic studies revealed that TUBB4B decrease is accompanied by cell elongation and increased number of matured focal adhesion sites, which is a characteristic of the cell metastatic stage. We also demonstrated faster polymerization of microtubules in cells with a lower level of TUBB4B. Simultaneous TUBB3 upregulation, reported during EMT, acts additively in this process. Our studies suggest that the protein level of TUBB4B could be used as a marker for detection of the preinvasive stages of the colon cancer cells. We also concluded that chemotherapy enriched to increase TUBB4B level and/or to stabilize microtubule polymerization might more effectively prevent metastasis in colon cancer development.
Highlights
Colon cancer is the third most cancer commonly diagnosed cancer worldwide
To follow the hypothesis that TUBB4B is downregulated during mesenchymal transdifferentiation, we analyzed the expression of beta-tubulins in two epithelial-mesenchymal transition (EMT) cellular models (Figure 1): HT-29 and LS180 cell lines stimulated by TGF-β1 (5 ng/mL for 48 h) [22] or overexpressed transcriptional factor Snail (HT-29/Snail and LS180/Snail)
Upregulation of TUBB3 observed during EMT is crucial for establishing the mesenchymal character of colon cancer cells. This involvement manifests itself in the regulation of the cell elongation and vimentin-microtubules interaction that is responsible for the cell polarity and increased cell migration
Summary
Colon cancer is the third most cancer commonly diagnosed cancer worldwide. Despite widespread screening, it is frequently diagnosed at metastatic stages and remains the second leading cause of cancer-related death [1]. A critical process associated with the tumor metastasis is the epithelial-mesenchymal transition (EMT) of the cancer cells [2]. The complex of filaments composed of microfilaments, microtubules, and intermediated filaments are connected to each other via the proteins interacting with them, causing the cytoskeleton to be seen as a single functional unit. In contrast to the well-described role of actin microfilaments in mesenchymal transdifferentiation [3], the relevance of microtubules and intermediate filaments during EMT is not fully understood
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