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Hsp60 is a chaperone belonging to the Chaperonins of Group I and typically functions inside mitochondria in which, together with the co-chaperonin Hsp10, maintains protein homeostasis. In addition to this canonical role, Hsp60 plays many others beyond the mitochondria, for instance in the cytosol, plasma-cell membrane, extracellular space, and body fluids. These non-canonical functions include participation in inflammation, autoimmunity, carcinogenesis, cell replication, and other cellular events in health and disease. Thus, Hsp60 is a multifaceted molecule with a wide range of cellular and tissue locations and functions, which is noteworthy because there is only one hsp60 gene. The question is by what mechanism this protein can become multifaceted. Likely, one factor contributing to this diversity is post-translational modification (PTM). The amino acid sequence of Hsp60 contains many potential phosphorylation sites, and other PTMs are possible such as O-GlcNAcylation, nitration, acetylation, S-nitrosylation, citrullination, oxidation, and ubiquitination. The effect of some of these PTMs on Hsp60 functions have been examined, for instance phosphorylation has been implicated in sperm capacitation, docking of H2B and microtubule-associated proteins, mitochondrial dysfunction, tumor invasiveness, and delay or facilitation of apoptosis. Nitration was found to affect the stability of the mitochondrial permeability transition pore, to inhibit folding ability, and to perturb insulin secretion. Hyperacetylation was associated with mitochondrial failure; S-nitrosylation has an impact on mitochondrial stability and endothelial integrity; citrullination can be pro-apoptotic; oxidation has a role in the response to cellular injury and in cell migration; and ubiquitination regulates interaction with the ubiquitin-proteasome system. Future research ought to determine which PTM causes which variations in the Hsp60 molecular properties and functions, and which of them are pathogenic, causing chaperonopathies. This is an important topic considering the number of acquired Hsp60 chaperonopathies already cataloged, many of which are serious diseases without efficacious treatment.

Hsp60 is one of the most ancient and evolutionarily conserved members of the chaperoning system. It typically resides within mitochondria, in which it contributes to maintaining the organelle’s proteome integrity and homeostasis. In the last few years, it has been shown that Hsp60 also occurs in other locations, intracellularly and extracellularly, including cytosol, plasma-cell membrane, and extracellular vesicles (EVs). Consequently, non-canonical functions and interacting partners of Hsp60 have been identified and it has been realized that it is a hub molecule in diverse networks and pathways and that it is implicated, directly or indirectly, in the development of various pathological conditions, the Hsp60 chaperonopathies. In this review, we will focus on the multi-faceted role of this chaperonin in human cancers, showing the contribution of intra- and extracellular Hsp60 in cancer development and progression, as well as the impact of miRNA-mediated regulation of Hsp60 in carcinogenesis. There are still various aspects of this intricate biological scenario that are poorly understood but ongoing research is steadily providing new insights and we will direct attention to them. For instance, we will highlight the possible applications of the Hsp60 involvement in carcinogenesis not only in diagnosis, but also in the development of specific anti-cancer therapies centered on the use of the chaperonin as therapeutic target or agent and depending on its role, pro- or anti-tumor.

Hsp27, Hsp60, Hsp70, and Hsp90 are chaperones that play a crucial role in cellular homeostasis and differentiation, but they may be implicated in carcinogenesis. Follicular neoplasms of the thyroid include follicular adenoma and follicular carcinoma. The former is a very frequent benign encapsulated nodule, whereas the other is a nodule that infiltrates the capsule, blood vessels and the adjacent parenchyma, with a tendency to metastasize. The main objective was to assess the potential of the Hsps in differential diagnosis and carcinogenesis. We quantified by immunohistochemistry Hsp27, Hsp60, Hsp70, and Hsp90 on thin sections of human thyroid tissue with follicular adenoma or follicular carcinoma, comparing the tumor with the adjacent peritumoral tissue. Hsp60, Hsp70, and Hsp90 were increased in follicular carcinoma compared to follicular adenoma, while Hsp27 showed no difference. Histochemical quantification of Hsp60, Hsp70, and Hsp90 allows diagnostic distinction between follicular adenoma and carcinoma, and between tumor and adjacent non-tumoral tissue. The quantitative variations of these chaperones in follicular carcinoma suggest their involvement in tumorigenesis, for instance in processes such as invasion of thyroid parenchyma and metastasization.