Resveratrol Inhibits the Tumorigenesis of Follicular Thyroid Cancer via ST6GAL2-Regulated Activation of the Hippo Signaling Pathway

Abstract

Follicular thyroid carcinoma (FTC) is a common endocrine malignancy with highly aggressive features. In this study, next-generation sequencing technology was used to identify aberrant expression of sialyltransferase (ST) family members in FTC. Aberrant high expression of alpha-2,6-sialyltransferase 2 (ST6GAL2) was demonstrated to promote tumorigenesis of FTC in vitro and in vivo. Furthermore, ST6GAL2 promoted tumorigenesis by inactivating the Hippo signaling pathway. Resveratrol is a native compound extracted from Vitis species, and many studies have confirmed its protective cardiovascular and antineoplastic effects. Here we found that resveratrol can inhibit the tumorigenesis of FTC by suppressing the expression of ST6GAL2, further activating the Hippo pathway. In summary, this study revealed the role of the ST6GAL2-Hippo signaling pathway in FTC tumorigenesis and indicated that resveratrol, a commonly found antineoplastic compound, could inhibit tumorigenesis of FTC by regulating the abovementioned pathways.Recently, sialyltransferase (ST) families have been reported to be critical cancer-regulating factors. 10 Sialylation is a key process in eukaryotic cells that has been shown to act in cell recognition, cell adhesion, receptor activation, and protein stability. 11 Therefore, STs contribute greatly to tumor development by acting as catalysts of sialylation. STs are categorized into four families: ST3GAL, ST6GAL, ST6GALNAC, and ST8SIA. 12 As reported, ST6GAL1 and ST3GAL6 regulate tumorigenesis of human colorectal carcinoma, 13,14 ST6GALNAC2 regulates breast cancer invasion, 15 and ST8SIA2 regulates cell invasion of non-small cell lung cancer. 16 Moreover, similar findings were reported in our previous study, which showed that alpha-2,6-sialyltransferase 2 (ST6GAL2) is highly expressed in FTC and regulated by the long noncoding RNA-HLA complex P5 (HCP5). 17 However, the downstream regulatory mechanisms of ST6GAL2 in FTC are not clear.

Glycation Interferes with the Expression of Sialyltransferases in Meningiomas

“…The downregulation of ST6GAL1 decreased metalloproteinases (MMPs) expression and suppressed invasive potential of A549 and H1299 cells in vitro [ 79 ], whereas bladder cancer has ST6GAL1 upregulation, a tumor-suppressive role [ 81 ]. The upregulation of ST6GAL2 was found in different types of cancer and was associated with breast cancer with higher expression of intracellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, CD24, MMP2, MMP9 and C-X-C motif chemokine receptor (CXCR)4 [ 82 , 83 ].…”

The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology

“…ST6GAL2 is predominantly expressed in the adult brain and fetal tissues, and to a lesser extent in the thyroid gland, small intestine, colon, and testis (147,148). While relatively few studies have investigated the expression and role of ST6GAL2 in tumors, overexpression of this enzyme was found in select types of cancer, including breast cancer (149) and follicular thyroid carcinoma (FTC) (150). In breast cancer ST6GAL2 expression associated with poor prognosis for patients (149).…”

Resveratrol and Resveratrol-Aspirin Hybrid Compounds as Potent Intestinal Anti-Inflammatory and Anti-Tumor Drugs

“…Previous reports have confirmed our observations including a recent publication by Sudha et al (2020) [ 52 ] to demonstrate tumor reduction by resveratrol and publications by Wang et al (2019) [ 53 ] and Zhang et al (2019) [ 54 ] that demonstrated the beneficial effect of resveratrol on DSS-induced colitis but at 80,100 mg/kg resveratrol use. In addition, cell-based modulation of follicular tumorigenesis (at 300 µM) [ 55 ] highlights the importance of our findings at 50–100 µM for our resveratrol derivatives. Because of the effectiveness of several aspirin-resveratrol derivatives towards both growth and NFκB inhibition (such as C3 and C11), these aspirin-resveratrol derivatives could be potent inhibitors of inflammation-driven malignant transformation.…”