Background: Thyroid cancer (TC) is the most prevalent endocrine malignancy, and is categorized into well-differentiated and aggressive anaplastic types. Novel therapeutic modalities are needed for TC. Nanomedicine is a promising strategy for the development of precision medicine. In this context, we investigated the use of nanogels (NGs) to deliver agents with different physicochemical properties, specifically the hydrophilic agent doxorubicin (DOX) and the hydrophobic compound curcumin (CUR), in TC cell lines. Methods: Nα-9-fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) peptide-based NGs loaded with DOX and CUR were formulated using the solvent-switch method. DOX-loaded NGs were previously characterized. CUR-loaded NGs were characterized through rheology, scanning electron microscopy (SEM), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), and Fourier transform infrared (FT-IR) spectroscopy. Confocal microscopy, q-RT-PCR, and ATP lite assays were performed to evaluate the uptake and delivery of DOX- and CUR-loaded NGs on TC cell lines. Results: CUR-loaded NGs exhibited a mean diameter of approximately 204.3 nm and a zeta potential of −34.6 mV, indicative of a good stability. In vitro release studies revealed a sustained release profile of CUR over 72 h. Functional analyses demonstrated that Fmoc-FF-loaded NGs were internalized into TC cell lines. They were primarily localized in the cytoplasm rather than in early endosomes, thereby ensuring intracellular stability. Furthermore, Fmoc-FF NGs reduced the nuclear uptake kinetics of DOX in TC cells, suggesting a potential reduction in dose-limiting toxicity. Comparative studies with CUR-loaded NGs revealed similar internalization and delayed nuclear uptake, highlighting the efficacy of Fmoc-FF NGs in delivering hydrophobic agents. Conclusions: Overall, the data suggest that Fmoc-FF NGs represent a promising strategy for delivering agents with diverse physicochemical properties in TC, enhancing their efficacy and safety and warranting further investigation.

Thyroid carcinoma is the most common endocrine cancer and includes different forms. Among these, anaplastic thyroid carcinoma (ATC) is the rarest but the most lethal subtype, compared to papillary thyroid carcinoma (PTC) which shows an overall good prognosis. We have previously showed that Tumor Suppressor Candidate 2 (TUSC2), a known tumour suppressor gene, is downregulated in human PTC and ATC compared to normal thyroid samples. The aim of this study was to gain insight into the molecular mechanisms induced by TUSC2 in thyroid cancer cells. Here, we stably transfected TUSC2 in papillary (TPC-1) and in anaplastic (8505C) thyroid cancer cell lines and studied its effects on several biological processes, demonstrating that TUSC2 overexpression decreased thyroid cancer cell proliferation, migration and invasion. Through the proteome profiler apoptosis array, we observed that TUSC2 increased sensitivity to apoptosis by increasing the SMAC/DIABLO and CYTOCHROME C proteins. On the other hand, transient silencing of TUSC2, by siRNA, in an immortalized thyroid follicular epithelial cell line (Nthy-ori 3-1) showed the opposite effect. Finally modulation of SMAC/DIABLO partially rescued the biological effects of TUSC2. Thus, our data highlight a tumour suppressor role of TUSC2 in thyroid carcinogenesis, suggesting that it could be a promising target and biomarker for thyroid carcinoma.

During tumorigenesis, miRNAs with unbalanced expression profiles can increase the threat of disease progression. Here, we focus on the role of miR-331-5p in the pathogenesis of thyroid cancer (TC). In vitro studies were conducted using TC cell lines after the forced expression and silencing of miR-331-5p. Cell proliferation and viability were analyzed via cell counts and colorimetric assays. Cell motility was analyzed via wound healing assays, Transwell migration and invasion assays, and Matrigel Matrix assays. The putative targets of miR-331-5p were unveiled via label-free proteomic screening and then verified using Western blot and luciferase assays. Expression studies were conducted by interrogating The Cancer Genome Atlas (TCGA). We found that ectopic miR-331-5p expression reduces TC cell motility, while miR-331-5p silencing induces the opposite phenotype. Proteomic screening revealed eight putative downregulated targets of miR-331-5p, among which BID was confirmed as a direct target. TCGA data showed the downregulation of miR-331-5p and the upregulation of BID in TC tissues. In summary, deregulation of the miR-331-5p/BID axis could enhance the aggressiveness of TC cell lines, providing new insights into the mechanisms of the progression of this disease and suggesting a potential role of the component factors as possible biomarkers in TC tissues.

Among natural macromolecules, the polyphenol extract from Annurca flesh (AFPE) apple could play a potential therapeutic role for a large spectrum of human cancer also by exerting antioxidant properties. Thyroid cancer is a common neoplasia in women, and it is in general responsive to treatments although patients may relapse and metastasize or therapy‐related side effects could occur. In this study, we explored the effects of AFPE on papillary (TPC‐1) and anaplastic (CAL62) thyroid cancer cell line proliferation and viability. We found that AFPE exposure induced a reduction of cell proliferation and cell viability in dose‐dependent manner. The effect was associated with the reduction of phosphorylation of Rb protein. To study the mechanisms underlying the biological effects of AFPE treatment in thyroid cancer cells, we investigated the modulation of miRNA (miR) expression. We found that AFPE treatment increased the expression of the miR‐141, miR‐145, miR‐200a‐5p, miR‐425, and miR‐551b‐5p. Additionally, since natural polyphenols could exert their beneficial effects through the antioxidant properties, we investigated this aspect, and we found that AFPE treatment reduced the production of reactive oxygen species (ROS) in CAL62 cells. Moreover, AFPE pretreatment protects against hydrogen peroxide‐induced oxidative stress in thyroid cancer cell lines. Taken together, our findings suggest that AFPE, by acting at micromolar concentration in thyroid cancer cell lines, may be considered a promising adjuvant natural agent for thyroid cancer treatment approach.

Among the non-coding RNAs, the aberrant expression of microRNAs (miRNAs) is well described in the oncology field. It is clear that the altered expression of miRNAs is crucial for a variety of processes such as proliferation, apoptosis, motility, angiogenesis and metastasis insurgence. Considering these aspects, RNA-based therapies and the use of miRNAs as non-invasive biomarkers for early diagnosis are underlined as promising opportunities against cancer death. In the era of precision medicine, significant progress in next-generation sequencing (NGS) techniques has broadened knowledge regarding the miRNAs expression profile in cancer tissues and in the blood of cancer patients. In this scenario, pre-clinical and clinical studies suggested that the members of the miR-584 family, i.e., miR-584-5p and -3p, are prominent players in cancer development and progression. Under some conditions, these miRNAs are under-expressed in cancer tissues acting as tumor suppressors, while in other conditions, they are overexpressed, acting as oncogenes increasing the aggressive behavior of cancer cells. The aim of this review is to provide a comprehensive and up-to-date overview on the expression, upstream genes, molecular targets and signaling pathways influenced by the miR-584 family (i.e., miR-584-3p and -5p) in various human solid and hematological cancers. To achieve this goal, 64 articles on this topic are discussed. Among these articles, 55 are focused on miR-584-5p, and it is outlined how this miRNA could be used in future applications as a potential new therapeutic strategy and diagnostic tool.

Increasing evidence revealed that restoring the correct expression of lncRNAs could have implications in the management of melanoma patients. In this context, here, we aim to dissect the main characteristics of lncRNAs altered in melanoma and their crosstalk with the signaling pathways involved in the progression of this disease. We also highlight the role of nucleic acid-based techniques and natural compounds (i.e., phytochemicals) as a therapeutic tool to increase or silence their expression in cancer cells. Finally, we explore the advances in nanotechnologies as delivery systems to efficiently carry these chemicals into cancer cells, thus limiting their potential off-target effects. The analysis of the literature showed that HOTAIR, MALAT1, and H19 are the oncogenic lncRNAs most studied in melanoma, while MEG3 is an important tumor suppressor decreased in this cancer. The aberrant expression of these lncRNAs affects several hallmarks of cancer, e.g., proliferation, motility, and epithelial to mesenchymal transition, promoting the melanoma plasticity and drug resistance. In this frame, siRNA, antisense oligonucleotide, and CRISPR-Cas9 genome editing appear to be the most effective nucleic acid strategies to restore the physiologic expression of lncRNA, while curcumin, resveratrol, and quercetin are the main phytochemicals able to target and influence the expression of lncRNAs altered in cancer. Overall, this study provides a comprehensive overview regarding the role of lncRNAs in the phenotype plasticity of melanoma cells and their potential targeting using RNA-based therapy and natural products.