miR145 Targets the SOX9/ADAM17 Axis to Inhibit Tumor-Initiating Cells and IL-6–Mediated Paracrine Effects in Head and Neck Cancer

Abstract

ALDH1þ CD44 þ cells are putative tumor-initiating cells (TIC) in head and neck squamous cell carcinomas (HNC). miR-145 regulates tumorigenicity in various cancers but the breadth of its mechanistic contributions and potential therapeutic applications are not completely known. Here, we report that ALDH1 þ CD44 þ -HNC cells express reduced levels of miR145. SPONGE-mediated inhibition of miR-145 (Spg-miR145) was sufficient to drive tumor-initiating characteristics in non-TICs/ALDH1 À CD44-negative HNC cells. Mechanistic analyses identified SOX9 and ADAM17 as two novel miR145 targets relevant to this process. miR-145 expression repressed TICs in HNC in a manner associated with SOX9 interaction with the ADAM17 promoter, thereby activating ADAM17 expression. Notably, the SOX9/ADAM17 axis dominated the TIC-inducing activity of miR-145. Either miR-145 suppression or ADAM17 overexpression in non-TICs/ALDH1À CD44 À -HNC cells increased expression and secretion of interleukin (IL)-6 and soluble-IL-6 receptor (sIL-6R). Conversely, conditioned medium from SpgmiR145-transfected non-TICs/ALDH1 À CD44 À -HNC cells was sufficient to confer tumor-initiating properties in non-TICs/ALDH1À CD44 À -HNC and this effect could be abrogated by an IL-6-neutralizing antibody. We found that curcumin administration increased miR-145 promoter activity, thereby decreasing SOX9/ADAM17 expression and eliminating TICs in HNC cell populations. Delivery of lentivral-miR145 or orally administered curcumin blocked tumor progression in HNC-TICs in murine xenotransplant assays. Finally, immunohistochemical analyses of patient specimens confirmed that an miR-145 low /SOX9 high /ADAM17 high phenotype correlated with poor survival. Collectively, our results show how miR-145 targets the SOX9/ADAM17 axis to regulate TIC properties in HNC, and how altering this pathway may partly explain the anticancer effects of curcumin. By inhibiting IL-6 and sIL-6R as downstream effector cytokines in this pathway, miR-145 seems to suppress a paracrine signaling pathway in the tumor microenvironment that is vital to maintain TICs in HNC. Cancer Res; 73(11); 3425-40. Ó2013 AACR.

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

“…Here we demonstrated that miR-145 biogenesis can be regulated by lncRNA-LET/NF90 axis. Although it is known that miR-145 negatively regulates human embryonic stem cells and CSCs, it is unclear whether it regulates the stemness markers indirectly or directly (45)(46)(47)(48). We demonstrated in this report that in UBC cells KLF4 and HMGA2, two miR-145 targets, are responsible for miR-145 mediated inhibition of UBC cell stemness.…”

Aberrant expression of SOX9 is associated with gastrokine 1 inactivation in gastric cancers

“…1), suggesting that GKN1 may downregulate SOX9 expression by inhibiting the b-catenin signaling pathway. However, it has also been reported that additional regulatory molecules, including miR-145 and NF-jB subunit p65, also contribute to the regulation of SOX9 expression [18,19], Thus, additional studies are necessary to verify these initial observations.…”

Low miR-145 silenced by DNA methylation promotes NSCLC cell proliferation, migration and invasion by targeting mucin 1

“…3 Emerging evidence has shown that miRNAs are involved in cancer initiation and progression. 4 MiR-145 has been reported as an important tumor suppressor gene in ovarian carcinoma, 5,6,7 malignant pleural mesothelioma, 8 breast cancer, 9 pancreatic cancer, 10,11 liposarcoma, 12 colorectal cancer, 13,14,15,16 neuroblastoma, 17 breast cancer, 18,19,20,21 esophageal cancer, 22 bladder cancer, 23,24 urothelial cancer, 25 prostate cancer, 26,27 gastric cancer, 28 and head and neck cancer, 29 and other types. MiR-145 was also implicated in the progression of NSCLC; 30,31,32 however, its exact mechanism is not well established.…”