Let-7d miRNA Shows Both Antioncogenic and Oncogenic Functions in Osteosarcoma-Derived 3AB-OS Cancer Stem Cells

Dec 19, 2015Journal of cellular physiology

Let-7d miRNA may both suppress and promote cancer in bone tumor stem cells

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Abstract

Let-7d overexpression reduced cell proliferation by decreasing cyclin D2 and E2F2 while increasing p21 and p27 in osteosarcoma cancer stem cells.

Let-7d modulation decreased the ability of osteosarcoma cancer stem cells to form sarcospheres and colonies, which are linked to self-renewal.
Overexpression of let-7d resulted in lower expression of stemness genes, including Oct3/4, Sox2, Nanog, Lin28B, and HMGA2.
Let-7d induced a transition from a mesenchymal to an epithelial cell state, indicated by changes in cadherin and vimentin expression.
Interestingly, this transition was associated with increased migratory and invasive capacities, marked by elevated levels of MMP9, CXCR4, and VersicanV1.
Let-7d overexpression reduced the sensitivity of cancer stem cells to apoptosis from serum starvation and chemotherapy, alongside changes in caspase-3 and BCL2 levels.
The findings suggest that let-7d may play dual roles as both a tumor suppressor and an oncogene in osteosarcoma cancer stem cells.

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Osteosarcoma (OS), an aggressive highly invasive and metastatic bone-malignancy, shows therapy resistance and recurrence, two features that likely depend on cancer stem cells (CSCs), which hold both self-renewing and malignant potential. So, effective anticancer therapies against OS should specifically target and destroy CSCs. We previously found that the let-7d microRNA was downregulated in the 3AB-OS-CSCs, derived from the human OS-MG63 cells. Here, we aimed to assess whether let-7d modulation affected tumorigenic and stemness properties of these OS-CSCs. We found that let-7d-overexpression reduced cell proliferation by decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also decreased sarcosphere-and-colony forming ability, two features associated with self-renewing, and it reduced the expression of stemness genes, including Oct3/4, Sox2, Nanog, Lin28B, and HMGA2. Moreover, let-7d induced mesenchymal-to-epithelial-transition, as shown by both N-Cadherin-E-cadherin-switch and decrease in vimentin. Surprisingly, such switch was accompanied by enhanced migratory/invasive capacities, with a strong increase in MMP9, CXCR4 and VersicanV1. Let-7d- overexpression also reduced cell sensitivity to apoptosis induced by both serum-starvation and various chemotherapy drugs, concomitant with decrease in caspase-3 and increase in BCL2 expression. Our data suggest that let-7d in 3AB-OS-CSCs could induce plastic-transitions from CSCs-to-non-CSCs and vice-versa. To our knowledge this is the first study to comprehensively examine the expression and functions of let-7d in OS-CSCs. By showing that let-7d has both tumor suppressor and oncogenic functions in this context, our findings suggest that, before prospecting new therapeutic strategies based on let-7d modulation, it is urgent to better define its multiple functions. J. Cell. Physiol. 231: 1832-1841, 2016. © 2015 Wiley Periodicals, Inc.

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Let-7d miRNA Shows Both Antioncogenic and Oncogenic Functions in Osteosarcoma-Derived 3AB-OS Cancer Stem Cells

Abstract

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