Moreover, the latter study showed that megalin manifestation in melanoma cells was crucial for cell maintenance, since siRNA-mediated reduction of LRP2/megalin manifestation in melanoma cells significantly decreased their proliferation and survival rates [19]. Based on these findings, we may speculate that MT-I/II/megalin interactions contributed to the development of severe dysplasia and better survival of malignantly transformed cells in cervical squamous epithelium, but mechanisms need to be elucidated. high-grade squamous intraepithelial lesion (LSIL and HSIL). The data showed that in LSIL (cervical intraepithelial neoplasia CIN1; em N /em ?=?25) MTs were present only in basal and parabasal cells and that megalin was only weakly indicated. In HSIL (CIN2; em N /em ?=?15 and CIN 3/carcinoma in situ; em N /em ?=?15), however, overexpression and co-localization of MT with megalin were found in the entire hyperplastic epithelium. Moreover, megalin immunoreactivity appeared within the glandular epithelium and Propineb vascular endothelium, as well as on lymphatic cells in stroma. Besides, multiple megalin-positive cells indicated phosphorylated Akt1, implying that MT- and/or megalin-dependent prosurvival transmission transduction pathways might contribute to the development of severe cervical dysplasia. The data stress the diagnostic power of combined MT/megalin analysis in pre-cancer screening. Electronic supplementary material The online version of this article (10.1007/s00428-020-02947-w) TNFSF13B contains supplementary material, which is available to authorized users. Propineb strong class=”kwd-title” Keywords: Akt1/protein kinase B phosphorylation, Biomarkers, CIN lesions, low-density lipoprotein receptorCrelated protein-2, Metallothionein-I/II, Tumour microenvironment Intro Metallothioneins (MTs) are a family of phylogenetically highly conserved, cysteine-rich, small ( ?10?kDa) proteins, which are characterized by high affinity for d10 electron construction metals, including essential (Zn and Cu) and non-essential (Cd and Hg) trace elements [1, 2]. They were in the beginning regarded as the mediators of cellular detoxification of weighty metals such as Cd, Hg, Cu and Ag [3], but due to the high kinetic mobility of essential metals and rules of zinc availability to numerous cellular enzymes, signalling proteins and transcription factors, they are also involved in the rules of fundamental cellular processes, such as gene manifestation, differentiation, proliferation and apoptosis [1, 4]. In addition, because of the high cysteine content material, MTs protect cellular macromolecules from highly reactive compounds during oxidative stress and other types of tissue accidental injuries, acting as potent scavengers of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), superoxide (O2C), nitric oxide (NO) and hydroxyl (OH) radicals [5]. Importantly, exogenous MTs may also interact with multiligand, scavenger receptors belonging to the family of Propineb low-density lipoprotein receptor (LDL-R)Crelated proteins (LRPs), such as LRP-2/megalin and LRP-1/CD91. These endocytic receptors as a result mediate the cellular uptake, proteolysis and gene manifestation of MTs, or induce the activation of fresh, LRP-related molecular signalling pathways [6, 7]. With this context, it has been shown the MT/LRP2 relationships mediate several neuroprotective and neuroregenerative effects particularly in the central and peripheral nervous system [8C14]. Owing to their features, both MTs and LRPs have been extensively investigated as diagnostic and prognostic markers of various types of malignancy and Propineb factors implicated in processes of oncogenesis and tumour progression [16C21]. The data were related with the intercourse of MTs with zinc-dependent enzymes and transcription factors important for cell cycle rules and proliferation control, such as p53, nuclear element B (NFB) and PKC [20] and with the ability of MTs to protect cells against DNA damage, oxidative stress and apoptosis [2, 17, 18, 21], as well as with hypermethylation of the MT-promoter or mutation of additional genes [22]. It was emphasized that in malignancy cells, metallothioneins protecting functions might activate tumour progression and malignancy, but the results assorted and depended on the type, differentiation.