The microRNA-210-Stathmin1 Axis Decreases Cell Stiffness to Facilitate the Invasiveness of Colorectal Cancer Stem Cells

SIMPLE SUMMARY: Metastasis of tumor cells is the leading cause of death in cancer patients. Concurrent therapy with surgical removal of primary and metastatic lesions is the main approach for cancer therapy. Currently, therapeutic resistant properties of cancer stem cells (CSCs) are known to drive malignant cancer progression, including metastasis. Our study aimed to identify molecular tools dedicated to the detection and treatment of CSCs. We confirmed that microRNA-210-3p (miR-210) was upregulated in colorectal stem-like cancer cells, which targeted stathmin1 (STMN1), to decrease cell elasticity for increasing mobility. We envision that strategies for softening cellular elasticity will reduce the onset of CSC-orientated metastasis. ABSTRACT: Cell migration is critical for regional dissemination and distal metastasis of cancer cells, which remain the major causes of poor prognosis and death in patients with colorectal cancer (CRC). Although cytoskeletal dynamics and cellular deformability contribute to the migration of cancer cells and metastasis, the mechanisms governing the migratory ability of cancer stem cells (CSCs), a nongenetic source of tumor heterogeneity, are unclear. Here, we expanded colorectal CSCs (CRCSCs) as colonospheres and showed that CRCSCs exhibited higher cell motility in transwell migration assays and 3D invasion assays and greater deformability in particle tracking microrheology than did their parental CRC cells. Mechanistically, in CRCSCs, microRNA-210-3p (miR-210) targeted stathmin1 (STMN1), which is known for inducing microtubule destabilization, to decrease cell elasticity in order to facilitate cell motility without affecting the epithelial–mesenchymal transition (EMT) status. Clinically, the miR-210-STMN1 axis was activated in CRC patients with liver metastasis and correlated with a worse clinical outcome. This study elucidates a miRNA-oriented mechanism regulating the deformability of CRCSCs beyond the EMT process.