Sonic Hedgehog Signaling in Thyroid Cancer

Abstract

Thyroid cancer is the most common malignancy of the endocrine system. The initiation of thyroid cancer is often triggered by a genetic mutation in the phosphortidylinositol-3 kinase (PI3K) or mitogen-activated protein kinase (MAPK) pathway, such as RAS and BRAF, or by the rearrangement of growth factor receptor tyrosine kinase genes such as RET/PTC. The sonic hedgehog (Shh) pathway is evolutionarily conserved and plays an important role in the embryonic development of normal tissues and organs. Gene mutations in the Shh pathway are involved in basal cell carcinomas (BCC). Activation of the Shh pathway due to overexpression of the genes encoding the components of this pathway stimulates the growth and spread of a wide range of cancer types. The Shh pathway also plays an important role in cancer stem cell (CSC) self-renewal. GDC-0449 and LDE-225, two inhibitors of this pathway, have been approved for treating BCC and are being tested as a single agent or in combination with other drugs for treating various other cancers. Here, we review the recent findings on activation of the Shh pathway in thyroid cancer and its role in maintaining thyroid CSC self-renewal. We also summarize the recent developments on crosstalk of the Shh pathway with the MAPK and PI3K oncogenic pathways, and its implications for combination therapy.

Keywords: BRAF; MAP kinase signaling system; cancer stem cells; phosphortidylinositol-3 kinase; sonic hedgehog; thyroid neoplasms.

Figure 1

The sonic hedgehog (Shh) signaling pathway in a mammalian system. Hedgehog (HH) ligand proteins are processed in the cytosol by autoproteolytical cleavage to generate an N-terminal subunit, which is further modified by the addition of palmitoyl and cholesterol moieties. The lipidated Shh is stored in the lipid-rich microdomain on the cell surface but is released by cooperative action of Dispatched and Scube 2. In the absence of ligand binding, Patched (Ptch) restrains Smoothened (Smo) in the cytosol and keeps it as an inactive dimer. Glioma-associated oncogene (Gli) is located at the ciliary tip where it interacts with and is repressed by Suppressor of fused (SuFu). Upon HH binding, Ptch releases Smo and allows it to translocate into the cytoplasmic membrane of the ciliary tip where it cooperates with KIF3a and Arrb2 to disrupt the interaction of SuFu and Gli. Freed Gli is then translocated into the nucleus to activate the transcription of its target genes such as Snail, Shh, and Ptch.

Figure 2

Non-canonical activation of the sonic hedgehog (Shh) pathway. Growth factor binding to their receptors activates two prominent oncogenic pathways, the phosphortidylinositol-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. In addition to the canonical activation, Gli1 can be activated by S6 kinase 1 (S6K1)-mediated phosphorylation at Serine 84, leading to nuclear translocation and induction of gene transcription. Gli1 can also be activated by ERK, probably through phosphorylation of its N-terminus by ERK2. Gli2 activity can be regulated by the MAPK pathway through increasing its stability. In addition, the MAPK pathway can activate the Shh pathway by inducing Shh expression through transcriptional upregulation. Gli1 can reciprocally activate the PI3K pathway indirectly by inducing Bmi1 expression, which represses PTEN expression. Crosstalk between the Shh and other oncogenic pathways regulates a variety of cellular functions, including cell proliferation, cell cycle progress, epithelial-to-mesenchymal transition, cell motility and invasiveness, and cancer stem cell (CSC) self-renewal.

Figure 3

Regulation of thyroid cancer stem cell (CSC) self-renewal by the sonic hedgehog (Shh) pathway. Canonical or non-canonical Gli activation induces Snail expression. Gli1 and Snail may directly induce Bmi1 expression or indirectly induce Bmi1 expression through miRNAs, such as miR-128 or miR-218. Bmi1 is a master regulator that controls the expression of several stem cell-related genes, such as Sox2 and Nanog, and CSC self-renewal.