Gene expression and pathway bioinformatics analysis detect a potential predictive value of MAP3K8 in thyroid cancer progression

📝 Abstract

Thyroid cancer is the commonest endocrine malignancy. Mutation in the BRAF serine/threonine kinase is the most frequent genetic alteration in thyroid cancer. Target therapy for advanced and poorly differentiated thyroid carcinomas include BRAF pathway inhibitors. Here, we evaluated the role of MAP3K8 expression as a potential driver of resistance to BRAF inhibition in thyroid cancer. By analyzing Gene Expression Omnibus data repository, across all thyroid cancer histotypes, we found that MAP3K8 is up-regulated in poorly differentiated thyroid carcinomas and its expression is related to a stem cell like phenotype and a poorer prognosis and survival. Taken together these data unravel a novel mechanism for thyroid cancer progression and chemo-resistance and confirm previous results obtained in cultured thyroid cancer stem cells

💡 Analysis

Thyroid cancer is the commonest endocrine malignancy. Mutation in the BRAF serine/threonine kinase is the most frequent genetic alteration in thyroid cancer. Target therapy for advanced and poorly differentiated thyroid carcinomas include BRAF pathway inhibitors. Here, we evaluated the role of MAP3K8 expression as a potential driver of resistance to BRAF inhibition in thyroid cancer. By analyzing Gene Expression Omnibus data repository, across all thyroid cancer histotypes, we found that MAP3K8 is up-regulated in poorly differentiated thyroid carcinomas and its expression is related to a stem cell like phenotype and a poorer prognosis and survival. Taken together these data unravel a novel mechanism for thyroid cancer progression and chemo-resistance and confirm previous results obtained in cultured thyroid cancer stem cells

📄 Content

Gene expression and pathway bioinformatics analysis detect a potential predictive value of MAP3K8 in thyroid cancer progression

Valentina Di Salvatore Dept. of Biomedical and Biotechnological Sciences University of Catania Catania, Italy valentina.disalvatore@unict.it

Giulia Russo Dept. Of Drug Sciences University of Catania, Catania, Italy giulia.russo@unict.it

Pasqualino Malandrino Dept. of Clinical and Experimental Medicine University of Catania Catania, Italy linomalandrino@gmail.com

Francesco Pappalardo Dept. Of Drug Sciences University of Catania, Catania, Italy francesco.pappalardo@unict.it

Fiorenza Gianì Dept. of Department of Clinical and Molecular BioMedicine, Garibaldi-Nesima Medical Center Catania, Italy fiorenza.giani@gmail.com

Marzio Pennisi Dept. of Mathematics and Computer Science University of Catania, Catania, Italy mpennisi@dmi.unict.it

Francesco Frasca Dept. of Department of Clinical and Molecular BioMedicine, Garibaldi-Nesima Medical Center Catania, Italy f.frasca@unict.it

Corresponding author: Francesco Pappalardo

Abstract— Thyroid cancer is the commonest endocrine malignancy. Mutation in the BRAF serine/threonine kinase is the most frequent genetic alteration in thyroid cancer. Target therapy for advanced and poorly differentiated thyroid carcinomas include BRAF pathway inhibitors. Here, we evaluated the role of MAP3K8 expression as a potential driver of resistance to BRAF inhibition in thyroid cancer. By analyzing Gene Expression Omnibus data repository, across all thyroid cancer histotypes, we found that MAP3K8 is up-regulated in poorly differentiated thyroid carcinomas and its expression is related to a stem cell like phenotype and a poorer prognosis and survival. Taken together these data unravel a novel mechanism for thyroid cancer progression and chemo-resistance and confirm previous results obtained in cultured thyroid cancer stem cells
Keywords—Thyroid cancer, BRAF, MAP3K8, pathway analysis

I. INTRODUCTION
Thyroid cancer is the most common type of endocrine tumor showing an increasing incidence over the last three decades. Malignant carcinoma of the thyroid arises from two different cell types, follicular and parafollicular. Follicular cells are involved in the production of thyroid hormones and they may give rise to well-differentiated and anaplastic thyroid carcinomas. The parafollicular C cells are responsible for the calcitonin production and they may give rise to medullary thyroid cancer (MTC) [1]. BRAF participates in the production of a protein involved in the transmission of chemical signals from outside the cell to the nucleus. This protein is part of the RAS/MAPK signaling pathway, which controls several important cell functions. Specifically, the RAS/MAPK pathway regulates cell proliferation, differentiation, migration and the programmed death (apoptosis) [2].
Among the various Raf kinase isoforms, the B-type RAF V600E (BRAFV600E) mutation is the most commonly observed inducing excessive proliferation and differentiation of tumor cells at the initial tumor stage [3]. Mutations in the BRAF serine/threonine kinase represent the most common genetic cause in thyroid cancer, occurring in approximately 45% of papillary thyroid cancer (PTC) and in a lower proportion of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) [4].
Moreover, BRAF gene mutations may be considered as a predictive factor for lymph node metastasis, extrathyroid extension, advanced disease stages III and IV, and disease recurrence [5].
The importance of the MAPK pathway has been well established in the tumorigenesis of PTC. The MAPK pathway is driven by activating mutations, including BRAF and RAS mutations, RET/PTC, TRK and ALK rearrangements. MAPK- mediated thyroid tumorigenesis involves a wide range of secondary molecular alterations that synergize and amplify the oncogenic activity of this pathway, such as genome-wide hypermethylation and hypomethylation and altered expression of miRNAs. Upregulation of various oncogenic proteins can occur and drive cancer cell proliferation, growth, migration and survival, as well as tumor angiogenesis, invasion and metastasis [6]. In a previous work we found that thyroid cancer stem cells derived from 8505 cell line are resistant to the BRAF inhibitor vemurafenib, despite harboring BRAFV600E mutation. In these cancer stem cells the resistance to vemurafenib was mediated by a paradoxical over-activation of ERK and AKT pathways. By our computational modeling, we found a fundamental role of mitogen-activated protein kinase 8 (MAP3K8), a serine/threonine kinase expressed in thyroid CSCs, in mediating this drug resistance. Hence, in this paper, we investigate the MAP3K8 expression in vivo in a large series of human thyroid cancer samples and its relationship to tumor behavio

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