Abstract
Anaplastic carcinoma of the thyroid (ATC), also called undifferentiated thyroid cancer, is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers. The aim of this study is to explore essential biomarker and use CRISPR/Cas9 with lentivirus delivery to establish a gene-target therapeutic platform in ATC cells. At the beginning, the gene expression datasets from 1036 cancers from CCLE and 8215 tumors from TCGA were collected and analyzed, showing EGFR is predominantly overexpressed in thyroid cancers than other type of cancers (P = 0.017 in CCLE and P = 0.001 in TCGA). Using CRISPR/Cas9 genomic edit system, ATC cells with EGFR sgRNA lentivirus transfection obtained great disruptions on gene and protein expression, resulting in cell cycle arrest, cell growth inhibition, and most importantly metastasis turn-off ability. In addition, the FDA-approved TKI of afatinib for EGFR targeting also illustrates great anticancer activity on cancer cell death occurrence, cell growth inhibition, and cell cycle arrest in SW579 cells, an EGFR expressing human ATC cell line. Furthermore, off-target effect of using EGFR sgRNAs was measured and found no genomic editing can be detected in off-target candidate gene. To conclude, this study provides potential ATC therapeutic strategies for current and future clinical needs, which may be possible in increasing the survival rate of ATC patients by translational medicine.
Highlights
Anaplastic carcinoma of the thyroid (ATC), called undifferentiated thyroid cancer, is the least common and most aggressive and deadly thyroid gland malignancy of all thyroid cancers
In order to investigate the expression of epidermal growth factor receptor (EGFR) family members in cancers, the gene expression profiles of 1036 cancer cells from CCLE database are classified into 24 tumor types (Figure 1(a))
As compared to the other 1024 cancer cells, the overall EGFR expression in 12 thyroid cancer cells is significantly overexpressed with 1.7-folds, whereas the overall expressions of ERBB2, ERBB4, and EGF show similar expressions in all cancer cells
Summary
Anaplastic carcinoma of the thyroid (ATC), called undifferentiated thyroid cancer, is the least common and most aggressive and deadly thyroid gland malignancy of all thyroid cancers. Patients are usually in their 60s–70s at presentation, having an average median survival of five months, and most patients with ATC do not live one year from the day they are diagnosed [1, 2]. Due to the extremely aggressive behavior of ATC, the American Joint Committee on Cancer (AJCC) defines all of its stages as stage IV [3]. No effective therapeutic options were available for patients with ATC resistant to radioiodine. Even the conventional therapies such as external beam radiotherapy and chemotherapy are not able to prolong survival either as a single therapeutic agent or as combination therapy strategy [4]
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