Role of AhR in regulating cancer stem cell–like characteristics in choriocarcinoma

Abstract

Choriocarcinoma is sensitive to chemotherapy. However, drug resistance has become one of the major problems in recent years. Previous studies have shown that many tumors contained a small fraction of cells that exhibited enhanced tumor initiating potential and stem cell-like properties. It is hypothesized that cancer stem cells (CSCs) are organized in a cellular hierarchy. They also have the qualities of selfrenewal, chemoresistance, and so on. The identification of CSCs in choriocarcinoma and the mechanism contributing to their qualities remain largely unknown. This study focused on the role of AhR, a transcription factor abundantly expressed in many different types of cancer, in the regulation of the expansion of choriocarcinoma CSCs and the exact molecular mechanisms. Spheroid cells isolated from choriocarcinoma in serum-free conditions have stem cell-like characteristics. The expression and nuclear translocation of AhR were markedly elevated in spheroid cells. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly increased the spheroid-forming efficiency, chemotherapy resistance, and ability to form tumor xenografts of the cells, whereas AhR knockdown, using short hairpin RNA (shRNA), dramatically reduced stem cell properties. Mechanistically, activating the β-catenin pathway might be an essential biological function of AhR during the regulation of the CSC characteristics. This study also identified ABCG2, which plays an important role in CSCs, as a direct target of AhR. Together, these results strongly suggested the participation of AhR in choriocarcinoma carcinogenesis. Targeting AhR may provide a novel therapeutic opportunity for choriocarcinoma. ARTICLE HISTORY

How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression

“…A rapidly enlarging body of evidence implicates the AHR in these processes. For example, in head and neck carcinoma, lung carcinoma, and choriocarcinoma cell lines, the AHR regulates expression of an ABC transporter, ABCG2, which contributes to chemoresistance by exporting drugs out of the cell against a concentration gradient [ 86 , 196 , 197 , 198 ]. AHR expression is elevated and nuclear in choriocarcinoma [ 197 ], TNBC [ 162 ], and oral squamous cell CSCs [ 106 ].…”

“…For example, in head and neck carcinoma, lung carcinoma, and choriocarcinoma cell lines, the AHR regulates expression of an ABC transporter, ABCG2, which contributes to chemoresistance by exporting drugs out of the cell against a concentration gradient [ 86 , 196 , 197 , 198 ]. AHR expression is elevated and nuclear in choriocarcinoma [ 197 ], TNBC [ 162 ], and oral squamous cell CSCs [ 106 ]. Similarly, in oral cancer and triple negative or ER + breast cancer cells, the AHR was shown to regulate aldehyde dehydrogenase (ALDH) [ 106 , 162 , 199 ], which, like ABCG2, is associated with chemotherapy export [ 200 ].…”

“…Functional studies are consistent with the findings on AHR-regulated stem cell genes. Thus, as would be predicted from the studies on ABCG2 and ALDH1, AHR inhibitors increased the sensitivity of ER + and ER - breast carcinoma cells to Adriamycin and Paclitaxel [ 162 , 199 ], oral cancer cells to Cisplatin [ 106 , 199 ] and choriocarcinoma cells to Methotrexate [ 197 ], directly connecting AHR-driven CSCs to cancer treatment outcomes. With regard to these studies, the ability of some of the chemotherapeutics (e.g., Cisplatin) to reduce AHR signaling in and of themselves, may have contributed to the increased effectiveness of the combination of AHR inhibitor and chemotherapeutics [ 205 ].…”

“…CSC-dependent low adherence spheroid formation of choriocarcinoma or breast carcinoma cells in vitro was suppressed with AHR inhibitors or AHR knockdown and increased with AHR agonists (e.g., TCDD) [ 162 , 197 , 199 ]. Importantly, AHR high /ALDH high breast cancer CSCs were significantly more efficient at initiating tumors than AHR low /ALDH low cells, and AHR knockdown with siRNA significantly reduced tumor-initiating capacity [ 162 ], a sine qua non of CSCs [ 207 ].…”

Inhibitory effect of dihydromyricetin on the proliferation of JAR cells and its mechanism of action

“…With advancements in multidrug combination chemotherapy, the cure rate of choriocarcinoma has significantly improved (4). However, some patients still fail to respond to treatment due to the strong proliferative and invasive abilities of choriocarcinoma, as well as the severe toxic side effects of chemotherapy, and multidrug resistance to chemotherapy (5). Thus, it is important to inhibit the proliferation and invasion of choriocarcinoma cells, and to explore new anticancer drugs with low toxicity and high efficiency.…”