JAK/STAT3 and NF-κB Signaling Pathways Regulate Cancer Stem-Cell Properties in Anaplastic Thyroid Cancer Cells

Abstract

Background: Anaplastic thyroid carcinoma (ATC) is still one of the most aggressive and refractory cancers, and a therapy with a new concept needs to be developed. Recently, the research of cancer stem cells (CSCs) has been progressed, and CSCs have been suggested to be responsible for metastasis, recurrence, and therapy resistance. In ATC-CSCs, aldehyde dehydrogenase (ALDH) activity is the most reliable marker to enrich the CSCs; however, it itself is just a marker and is not involved in CSC properties. In the present study, therefore, we aimed to identify key signaling pathways specific for ATC-CSCs. Methods: The siRNA library targeting 719 kinases was used in sphere formation assay and cell survival assay using ATC cell lines to select target molecules specific for the CSC properties. The functions of the selected candidates were confirmed by sphere formation, cell survival, soft-agar, and nude mice xenograft assays using small compound inhibitors. Results: We focused on PDGFR, JAK, and PIM, whose siRNAs had the higher inhibitory effect on sphere formation and also lower/no effect on regular cell growth in both FRO and KTC3 cells. Next, we used inhibitors of PDGFR, JAK, STAT3, PIM and NF-κB, and all of them successfully suppressed sphere formation in a dose-dependent manner but not regular cell growth, conforming the screening results. Inhibition of the JAK/STAT3 and NF-κB pathways also reduced anchorage-independent growth in soft agar and tumor growth in nude mice. Conclusions: These results suggest that JAK/STAT3 and NF-κB signals play important roles in ATC-CSCs. Targeting these signaling pathways may be a promising approach to treat ATC.

Synergy of GSK-J4 With Doxorubicin in KRAS-Mutant Anaplastic Thyroid Cancer

“…Sherry-Lynes et al found that the transcription regulator STAT3 can directly bind to the JMJD3 promoter, specifically inducing JMJD3 expression and resulting in demethylation of H3K27me3, thereby affecting the expression of downstream genes that have been proven to be related to chemosensitivity. Ken Shiraiwa et al suggested that STAT3 played an important role in ATC stem cells (Shiraiwa et al, 2019). After treatment with a STAT3 inhibitor, cancer cells were sensitized to chemotherapeutic drugs (Borbone et al, 2010).…”

Sanguinarine Induces Apoptosis in Papillary Thyroid Cancer Cells via Generation of Reactive Oxygen Species

“…Cancer stem-like cells are the small population of cells within the tumor that are well known for their important role in carcinogenesis, cancer resistance, recurrence and self-renewal [13,69,70]. Among the many laboratory models in use for the study of cancer stem-like cells, the one involving the growth of cancer cells on ultralow attachment plates is a widely accepted model for the generation of spheres.…”

“…Cancer stem cells (CSCs) are a small population of cells present in tumors that play a critical role in cancer resistance, relapse, tumorigenesis and poor clinical outcomes [13]. This information led us to investigate whether SNG can suppress the stemness of PTC CSC-like cells derived from BCPAP and TPC-1 spheroids (thyrospheres).…”

“…It has now become evident that dysregulated STAT3, vital for the expression and functioning of genes required for cell survival and development, including immunity and stemness, is a crucial target to overcome the cancer pathogenesis and related challenges [8][9][10][11]. The role of STAT3 in thyroid malignancies is relatively less studied, however, there are data from some in vitro as well as in vivo studies [12][13][14][15], including the recent investigations on how STAT3 plays a critical role in noncoding RNA-mediated alterations related to the thyroid cancer pathogenesis [16][17][18]. In addition, the critical role of STAT3 in the development of both solid and hematological human malignancies has been reported by many research groups [19][20][21].…”

CCL21/CCR7 interaction promotes EMT and enhances the stemness of OSCC via a JAK2/STAT3 signaling pathway

“…Phosphorylated STATs then binds to specific DNA elements and activates gene transcription (Murray, 2014). Specifically, the JAK2/STAT3 signaling pathway plays crucial roles in the EMT, apoptosis, proliferation, and drug resistance of various cancers (B. Li & Huang, 2017; Yu, Gong, Li, Pan, & Zhang, 2018), and the activation of STAT3 is closely related to the stemness of cancer cells (Kuepper et al, 2019; Shiraiwa et al, 2019). However, whether the JAK2/STAT3 pathway regulates EMT and the stemness of OSCC remains unclear.…”