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

Abstract

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.

Let-7d Inhibits Growth and Metastasis in Breast Cancer by Targeting Jab1/Cops5

“…Direct targets of let-7 include oncogenes such as RAS and HMGA2 [23,32]. In the present study, we found expression of let-7d was lower in breast cancer tissue than in normal breast tissue.…”

“…On the other hand, let-7d contributes to the pathogenesis of some cancers. For instance, it was reported that let-7d exerted both anti-oncogenic and oncogenic effects in osteosarcoma [23]. Besides this, let-7d directly targeted CCL7, COL3A1, HMGA2 [23], and PBX3 [24,25], and inhibited cell growth, invasion, and metastasis.…”

miR-486 suppresses the development of osteosarcoma by regulating PKC-δ pathway

“…However, it is still difficult to solve the two major problems, the recurrence and metastasis. Approximately 80–90% of the causes of death in patients with osteosarcoma are metastasis especially pulmonary metastasis (1–3). Therefore, it is extremely urgent to find effective early diagnostic tools and treatment in osteosarcoma.…”

“…MiRNAs are proved to be related to the occurrence and the metastasis of osteosarcoma (1–3). miRNA expression in tumor cell lines and different clinical osteosarcoma samples were investigated and 22 differentially expressed miRNAs were found, among them the miRNAs miR-135b, miR-150, miR-542–5p and miR-652 have been verified and confirmed that may be involved in the tumor genesis of osteosarcoma (1).…”

USP17 is upregulated in osteosarcoma and promotes cell proliferation, metastasis, and epithelial–mesenchymal transition through stabilizing SMAD4

“…Almost 80%-90% of patients died due to pulmonary metastasis. [2][3][4] Therefore, it is urgent to understand the molecular mechanism of metastasis and find an effective therapeutic target to inhibit cancer cells' metastasis.…”