Abstract
Sox2 (Sry-box2) is essential for a variety of stem cells and is also expressed in colorectal cancer (CRC). However, the underlying mechanism by which Sox2 enhances CRC progression remains unclear. In the present study, we show that elevated Sox2 expression is significantly correlated with poor clinical prognosis. CRC is phenotypically heterogeneous, and harbors several subtypes of cancer cells. Elevated Sox2 expression was always detected in rounded-shape cells, which co-located to poorly differentiated regions, the invasive frontier and metastatic lesions. Knockdown of Sox2 in CRC cells not only decreased the number of round-shaped cells, but also suppressed cell migration, invasion as well as attenuated colony forming capacity and tumorigenicity. By contrast, overexpression of Sox2 in CRC cells was associated with up-regulation of multidrug resistance genes and accelerated CRC progression. Moreover, Sox2 conferred activation of Rho-ROCK signaling, whereas inhibition of ROCK signaling decreased cell migration, invasion, colony formation and self-renewal of CRC. Our results reveal that CRC is phenotypically and functionally heterogeneous. Elevated Sox2 expression activates the Rho-ROCK pathway, which in turn changes cell morphology and promotes cell migration and progression.
Highlights
Introduction50% of colorectal cancer (CRC) patients can be treated by surgery and multimodal treatment before disease progression
Colorectal cancer (CRC) is a major cause of cancerrelated deaths worldwide [1]
136 specimens, including colorectal cancer (CRC) tissues, paratumoral tissues, lymph node metastatic tissues and distant organ metastatic tissues were evaluated for the Sox2 expression by immunohistochemistry
Summary
50% of CRC patients can be treated by surgery and multimodal treatment before disease progression. 4050% of patients have metastatic disease which requires more aggressive treatment. Two different modes of cell movement are identified in individual tumor cells: a mesenchymal mode characterized by an elongated morphology that requires extracellular proteolysis localized at cellular protrusions and an amoeboid mode, in which movement is independent of proteases and typically these cells have a rounded morphology. Rho signals to ROCK, promoting the formation of actin stress fibers and generation of the actomyosin contractile force, whereas Rac and Cdc www.impactjournals.com/oncotarget drive motility by promoting lamellipodia formation [2, 3]. The amoeboid mode involves signaling through ROCK, whereas the mesenchymal mode requires extracellular proteolysis for Rac-dependent actin protrusions to be pushed through channels in the extracellular matrix [4]
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