Targeting the Sonic Hedgehog Pathway to Suppress the Expression of the Cancer Stem Cell (CSC)-Related Transcription Factors and CSC-Driven Thyroid Tumor Growth

Simple Summary Poorly differentiated and anaplastic thyroid cancers respond poorly to surgery, radiation, and hormone therapy. Cancer stem cells play an important role in tumor growth, drug resistance, and recurrence. This study focuses on how the sonic hedgehog (Shh) pathway maintains thyroid cancer stem cell self-renewal and whether it can be targeted for anticancer therapy. The authors report that the Shh pathway regulates the expression of BMI1 and SOX2, two genes involved in stem cell self-renewal, and that targeting the Shh pathway has little effect on thyroid tumor xenografts but can inhibit the growth of tumor xenografts derived from thyroid cancer stem cells. This study advances the knowledge on how thyroid cancer stem cells regenerate and highlights the potential therapeutic values of targeting the Shh pathway. The sonic hedgehog (Shh) pathway plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. We and others have reported earlier that this pathway is highly activated in thyroid cancer. However, its role in thyroid cancer stem cell (CSC) self-renewal and tumor development remains incompletely understood. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and SRY-Box Transcription Factor 2 (SOX2) are two CSC-related transcription factors that have been implicated in promoting CSC self-renewal. The objective of our current investigation was to determine the role of the Shh pathway in regulating BMI1 and SOX2 expression in thyroid cancer and promoting thyroid tumor growth and development. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 reduced BMI1 and SOX2 expression in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines. The opposite results were obtained in cells overexpressing Gli1 or its downstream transcription factor Snail. The Shh pathway regulated SOX2 and BMI1 expression at a transcriptional and post-transcriptional level, respectively. GANT61 treatment suppressed the growth of SW1736 CSC-derived tumor xenografts but did not significantly inhibit the growth of tumors grown from bulk tumor cells. Clinicopathological analyses of thyroid tumor specimens by immunohistochemical (IHC) staining revealed that BMI1 and SOX2 were highly expressed in thyroid cancer and correlated with Gli1 expression. Our study provides evidence that activation of the Shh pathway leads to increased BMI1 and SOX2 expression in thyroid cancer and promotes thyroid CSC-driven tumor initiation. Targeting the Shh pathway may have therapeutic value for treating thyroid cancer and preventing recurrence.

Automated summary

The Sonic Hedgehog (Shh) pathway plays a crucial role in regulating thyroid cancer stem cell self-renewal, with inhibition of this pathway showing potential in preventing tumor initiation driven by thyroid cancer stem cells.