Local control of TH action in cancer growth and stemness

Abstract

Non-melanoma skin cancers, including basal cell carcinoma (BCC), are keratinocyte-derived tumors, which represent the most frequent cancers worldwide. BCCs can cause significant tissue destruction by local invasion, which is particularly devastating since they usually develop in regions closed to the eyes, nose and ears. The aberrant Hedgehog (Hh) pathway is a pivotal defect implicated in BCC formation. Several studies have demonstrated functional cross-talk between thyroid hormone (TH) and Hh signaling. TH controls a number of cellular processes including cell proliferation, differentiation and survival/apoptosis. Intracellular TH concentration is not simply the mirror of circulating TH levels, but is determined by a balance between the activating and inactivating deiodinases enzymes, D2 and D3. In functional combinations, these regulatory molecules provide the ability to fine-tune TH action at cell level. TH deregulation is frequent in human tumors, in particular type 3 iodothyronine deiodinase (D3), the thyroid hormone (TH)-inactivating enzyme, is an oncofetal protein rarely expressed in adult life, but re-activated in proliferating and neoplastic contexts. By terminating TH action within the tumor microenvironment, D3 enhances cancer cell proliferation. We aimed to understand how the TH action regulates multiple aspects of tumorigenesis, ranging from cancer formation to progression. Here we describe reciprocal regulation between TH action and the cancer-associated microRNA-21 (miR21) in BCC skin tumors. We found that, besides being negatively regulated by TH at transcriptional level, miR21 attenuates the TH signal by increasing D3 levels. The ability of miR21 to positively regulate D3 was mediated by GRHL3, a tumor suppressor gene and a hitherto unrecognized D3 transcriptional inhibitor. Moreover, we found that keratinocyte-specific D3-depletion significantly reduced tumor growth in a BCC mouse model, which establishes the functional relevance of this network in vivo. A second aim of this study was to underscore the role of TH and deiodinase D3 in the control of skin CSCs behavior. In vivo and in vitro evidences demonstrate that TH represses the transcription of the stemness gene Sox9. Furthermore, D3-depletion causes a variation of number of CD34+ cells demonstrating that TH metabolism is important not only for the control of tumor growth and maintenance, but also for the behavior of CSCs. Elucidating the functional role of TH in the landscape of tumorigenesis is crucial for the use of hormonal regulation as a new tool in a therapeutic context.