CST6 promotes the aggressive phenotype of thyroid cancer through maintaining autophagy

Abstract Thyroid Cancer (TC) is the most common malignant tumor of the endocrine system. Cystatin M/E (CST6) has been demonstrated to have a multifaceted role in several types of cancers. However, its potential mechanisms in the progression of TC have not been fully identified. Our results revealed that CST6 expressions were upregulated in TC tissues and cells compared with normal thyroid tissues and cells. High expression of CST6 was negatively correlated with poor prognosis of thyroid cancer patients. Functional assays showed that CST6 promoted TC cells malignant phenotype, including proliferation, colony formation, migration, and invasion. Inhibition of CST6 remarkably alleviated tumor growth and metastasis of ATC xenografts in nude mouse and zebrafish model. CST6 showed interaction with cathepsin B (CTSB). CTSB knockdown profoundly inhibited the aggressive behavior of TC cells. Of note, loss of CST6 attenuated the activity of CTSB, which led to the decrease of autophagy progress. Collectively, our findings demonstrated an essential role of CST6 in the development of TC through CTSB-mediated autophagy.