Tumor cell dedifferentiation, reversing cells from well differentiated states to less differentiated states, is considered to be a specific characteristic of highly aggressive. Generally, poor differentiation tumor cells present faster proliferation and more invasive. Previous studies demonstrated that lots of proteins (such as COL2A1, CD44, and ALDH) and intricate signal pathways (including p38 MAPK, ERK1/2, PI3K signal pathways) are involved in dedifferentiation process[2-6]. In this case, dedifferentiated tumor cells would develop therapy escape and become resistant to traditional therapies, including radiotherapy and chemotherapy. Studies on breast cancer have shown that dedifferentiated breast cancer cells, which is also known as breast cancer stem cells (BCSCs), were more invasive, less sensitive to chemotherapy, and more likely to recur comparing to well differentiated breast cancer cells. Another case of tumor cell dedifferentiation is radioactive 131-iodine refractory differentiated thyroid cancer (RR-DTC), which has become a great challenge for clinical treatment since such cells have lost ability of iodine accumulation.
The mobility of thyroid cancer is increasing at the rate of 3.6% per year in recent decades. Thyroid cancer includes four pathological types: papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), medullary thyroid cancer (MTC), and anaplastic thyroid cancer (ATC). PTC and FTC are also called differentiated thyroid cancer (DTC), which has the ability of radioactive 131-iodine uptake. Most patients with DTC enjoy favorable prognosis after standard treatment, consisting of totally thyroidectomy to remove primary focus, radioactive 131-iodine treatment to clear residue and oral thyroid stimulating hormone for hormone replacement therapy. Radioactive 131-iodine treatment plays a crucial role in the course of treatment, which can not only clear residue but also detect systemic metastasis. However, there are about 15%-20% of patients with thyroid cancer suffer poor prognosis because their lesions or metastasis lymph nodes have lost the ability of radioactive 131-iodine up-take, which is known as previous mentioned RR-DTC.
Cases meeting any one of criteria following are defined as RR-DTC: 1. metastatic lesions do not take radioactive 131-iodine after the first time of thyroidectomy; 2. metastatic lesions lose the ability of radioactive 131-iodine uptake gradually during treatment course; 3.some of the metastatic lesions with the ability of radioactive 131-iodine uptake while others not; 4.metastatic lesions take radioactive 131-iodine but patients’ condition keep progressing. Because of disability of radioactive 131-iodine uptake, patients with RR-DTC usually have poor prognosis. It is reported that once being diagnosed with RR-DTC, median survival of these patients ranges from only 3 to 6 years. Clinically, oral targeted drugs (such as sorafinib and lenvatinib) and radioactive 125-iodine seeds implantation are taking as palliative therapy for RR-DTC patients in progression. Nevertheless, lenvatinib and sorafenib help extent progression free survival (PFS) of RR-DTC patients but make no sense of improving overall survival (OS) of them. In addition, most patients have to interrupt targeted therapy because of intolerant side effects[13, 14]. Therefore, further studies are required to clarify pathogenesis of RR-DTC, which might provide new therapies for these patients.
Previous studies on RR-DTC suggest that occurrence of RR-DTC is related to activation of MAPK signal pathway and PI3K signal pathway, which facilitate tumor growth by changing cellular microenvironment, promoting angiogenesis, stimulating cell proliferation, and so on[15-17]. What is more, as is known to all, poor differentiation of RR-DTC cells leads to disability of radioactive 131-iodine uptake, which is major barrier for effective treatment. KEGG database demonstrates that activation of MAPK/ERK signal pathway regulates cell differentiation in kinds of diseases, such as rhabdomyosarcoma and breast cancer. Therefore, it reminds us that activation of MAPK/ERK signal pathway may result in poor cell differentiation in thyroid cancer.
Chitinase-3-like 1(CHI3L1, Accession: P36222), which could regulate tumor growth by activating MAPK/ERK signal pathway, is reported to be over expressed in some malignant tumors, including prostate cancer, pancreatic cancer, and breast cancer[18, 19]. Luo D. et. found that CHI3L1 was highly expressed in DTC comparing to adjacent tissues. Based on previous studies, our study assumes that CHI3L1 might express higher in RR-DTC than in DTC, which leads to poor differentiation of RR-DTC by activating MAPK/ERK signal pathway.
Sodium-iodide symporter (NIS) is a key protein for accumulating iodine in thyroid cells. In well differentiated thyroid cancer cells, expression of NIS is significantly higher than that in RR-DTC[21, 22]. Seung Hyun Son.et proposed that transfecting NIS gene to thyroid cancer cells could significantly increase radioactive 131-iodine uptake. General speaking, expression level of NIS is considered to be positive related with cell differentiation in thyroid cancer.
We hypothesized that over expression of CHI3L1 is critical to poor cell differentiation, which would inhibit expression of NIS and decrease radioactive 131-iodine uptake in RR-DTC. In our study, DTC tissues were taken as control and the study found that CHI3L1 was significantly up-regulated in RR-DTC than in DTC. Furthermore, the study found that expression of NIS was significantly inhibited by CHI3L1, which may be potential therapeutic target for RR-DTC.