Molecular Chaperones and Thyroid Cancer

Abstract

Thyroid cancers are the most common of the endocrine system malignancies and progress must be made in the areas of differential diagnosis and treatment to improve patient management. Advances in the understanding of carcinogenic mechanisms have occurred in various fronts, including studies of the chaperone system (CS). Components of the CS are found to be quantitatively increased or decreased, and some correlations have been established between the quantitative changes and tumor type, prognosis, and response to treatment. These correlations provide the basis for identifying distinctive patterns useful in differential diagnosis and for planning experiments aiming at elucidating the role of the CS in tumorigenesis. Here, we discuss studies of the CS components in various thyroid cancers (TC). The chaperones belonging to the families of the small heat-shock proteins Hsp70 and Hsp90 and the chaperonin of Group I, Hsp60, have been quantified mostly by immunohistochemistry and Western blot in tumor and normal control tissues and in extracellular vesicles. Distinctive differences were revealed between the various thyroid tumor types. The most frequent finding was an increase in the chaperones, which can be attributed to the augmented need for chaperones the tumor cells have because of their accelerated metabolism, growth, and division rate. Thus, chaperones help the tumor cell rather than protect the patient, exemplifying chaperonopathies by mistake or collaborationism. This highlights the need for research on chaperonotherapy, namely the development of means to eliminate/inhibit pathogenic chaperones.

Keywords: Hsp27; Hsp60; Hsp70; Hsp90; chaperone system; chaperonopathies by mistake; chaperonotherapy; differential diagnosis; molecular chaperones; thyroid tumors.

Figure 3

Hsp90 is involved in cancer development in pathways critical for the cell growth, invasiveness, and survival. Hsp90 regulates the hypoxia-inducible factor (HIF)-1α activity [50] (A), and together with chaperone p23, binds the human telomerase reverse transcriptase (hTERT) [54] (B), causing evasion from apoptosis and metastasis. (C) The components of the PI3K/AKT/mTOR pathway are Hsp90 clients, indicating the chaperone’s role in the regulation of autophagy. Therefore, autophagy has a pro-survival function [32,49]. (D) The tumor necrosis factor receptor-associated protein 1 (TRAP1) is involved in TCs: it is thought to enhance ERK phosphorylation and cell cycle progression, leading to a dampening of apoptosis by activation of the RAS/RAF/ERK pathway [56].

Figure 1

Hsp27 regulates apoptosis. (A) Hsp27 can be upregulated by estrogen (E2) levels in human papillary thyroid cancer (PTC) cells that have a higher level of ERα than of ERβ. Overexpression of Hsp27 facilitates proliferation, conferring resistance to apoptosis through interaction with procaspase-3 [29,31]. (B) Hsp27(shown as HSPB1), acting as scaffold protein, modulates apoptosis through interaction with Akt. In this way, Hsp27 increases the interaction of Akt with its substrate, Bax, inhibiting Bax activation, oligomerization, and translocation to the mitochondria, thus inhibiting the release of cytochrome C. This prevents the correct formation and function of the apoptosome complex [34,35].

Figure 2

Hsp70 is involved in cancer development at multiple steps. (A) Hsp70 induces evasion from apoptosis, blocking PI3K/Akt signaling [43]. (B) Mortalin (also called HSPA9 or GRP75), localized in mitochondria, alters MEK/ERK signaling, ensuring cell survival [23].