Transglutaminase type 2 (TG2) is the most ubiquitously expressed and well characterized member of the transglutaminase family. It is a ubiquitous multifunctional enzyme implicated in the regulation of several cellular pathways that support the survival, death, and general homeostasis of eukaryotic cells. Due to its multiple localizations both inside and outside the cell, TG2 participates in the regulation of many crucial intracellular signaling cascades in a tissue- and cell-specific manner, making this enzyme an important player in disease development and progression. Moreover, TG2 is capable of modulating the tumor microenvironment, a process of dynamic tissue remodeling and biomechanical events, resulting in changes which influence tumor initiation, growth, and metastasis. Even if generally related to the Ca²⁺-dependent post-translational modification of proteins, a number of different biological functions have been ascribed to TG2, like those of a peptide isomerase, protein kinase, guanine nucleotide binder, and cytosolic–nuclear translocator. With respect to cancer, TG2′s role is controversial and highly debated; it has been described both as an anti- and pro-apoptotic factor and is linked to all the processes of tumorigenesis. However, numerous pieces of evidence support a tissue-specific role of TG2 so that it can assume both oncogenic and tumor-suppressive roles.

The process of protein folding is important to ensure the efficient functioning of cells. The capacity of a protein to attain the three-dimensional native conformation can impact its structure and function. Errors in this process result in the accumulation of misfolded proteins, which can contribute to the development of various diseases, including cancer. To prevent the pileup of misfolded proteins, a number of control systems have been developed over the course of evolution. In this scenario, a pivotal function has been attributed to molecular chaperones and the ubiquitin-proteasome degradation system. In this paper, we concentrate on molecular chaperones, with a particular focus on a family of heat shock proteins (HSPs), to highlight any potential correlation between their expression and function and the development of cancer. Hence, we have collected data from various public databases regarding the HSP70 protein family. By employing mRNA expression signatures, prognostic value analysis, and differentially expressed gene ontology analysis, we have elucidated the tumor-specific role of two members of the HSP70 family, namely HSPA8 and HSPA9, in kidney renal clear cell carcinoma (KIRC), colon adenocarcinoma (COAD), and breast invasive carcinoma (BRCA). Our research shed light on the controversial and tumor-specific role of HSP70s. More in detail, we have identified HSPA8 and HSPA9 as potential prognostic and therapeutic targets involved in several biological processes leading to tumorigenesis, including nucleic acid maturation, cell signaling, vesicle trafficking, mitochondrial structure and function, and protein maturation.