MicroRNAs (miRNAs) have emerged as a class of powerful gene expression regulators. Acting at the post-transcriptional level, miRNAs modulate the expression of at least one-third of the mRNAs that are ...encoded by the human genome. The expression of a single gene can be regulated by several miRNAs, and every miRNA has more than one target gene. Thus, the miRNA regulatory circuit, which affects essential cellular functions, is of enormous complexity. Moreover, a fundamental role for miRNAs has been determined in the onset and progression of human cancers. Here, we summarize the main alterations in miRNA expression that have been identified in thyroid neoplasias and examine the mechanisms through which miRNA deregulation might promote thyroid cell transformation. We also discuss how the emerging knowledge on miRNA deregulation could be harnessed for the diagnosis and treatment of thyroid neoplasias.
Almost 30 years ago, overexpression of HMGA proteins was associated with malignant phenotype of rat thyroid cells transformed with murine retroviruses. Thereafter, several studies have analyzed HMGA ...expression in a wide range of human neoplasias. Here, we summarize all these results that, in the large majority of the cases, confirm the association of HMGA overexpression with high malignant phenotype as outlined by chemoresistance, spreading of metastases, and a global poor survival. Even though HMGA proteins' overexpression indicates a poor prognosis in almost all malignancies, their detection may be particularly useful in determining the prognosis of breast, lung, and colon carcinomas, suggesting for the treatment a more aggressive therapy. In particular, the expression of HMGA2 in lung carcinomas is frequently associated with the presence of metastases. Moreover, recent data revealed that often the cause for the high HMGA proteins levels detected in human malignancies is a deregulated expression of non-coding RNA. Therefore, the HMGA proteins represent tumor markers whose detection can be a valid tool for the diagnosis and prognosis of neoplastic diseases.
HMGA and Cancer: A Review on Patent Literatures De Martino, Marco; Fusco, Alfredo; Esposito, Francesco
Recent patents on anti-cancer drug discovery,
01/2019, Letnik:
14, Številka:
3
Journal Article
Recenzirano
The high mobility group A proteins modulate the transcription of numerous genes by interacting with transcription factors and/or altering the structure of chromatin. These proteins are involved in ...both benign and malignant neoplasias as a result of several pathways. A large amount of benign human mesenchymal tumors has rearrangements of HMGA genes. On the contrary, malignant tumors show unarranged HMGA overexpression that is frequently and causally related to neoplastic cell transformation. Here, we review the function of the HMGA proteins in human neoplastic disorders, the pathways by which they contribute to carcinogenesis and the new patents focused on targeting HMGA proteins.
Current review was conducted to check the involvement of HMGA as a druggable target in cancer treatment.
We reviewed the most recent patents focused on targeting HMGA in cancer treatment analyzing patent literature published during the last years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents.
HMGA proteins are intriguing targets for cancer therapy and are objects of different patents based on the use of DNA aptamers, inhibitors, oncolytic viruses, antisense molecules able to block their oncogenic functions.
Powerful strategies able to selectively interfere with HMGA expression and function could represent a helpful approach in the development of new anti-cancer therapies.
Papillary thyroid carcinoma (PTC) is frequently associated with RET gene rearrangements that generate the so-called RET/PTC oncogenes. In this review, we examine the data about the mechanisms of ...thyroid cell transformation, activation of downstream signal transduction pathways and modulation of gene expression induced by RET/PTC. These findings have advanced our understanding of the processes underlying PTC formation and provide the basis for novel therapeutic approaches to this disease.
Context:
We have previously demonstrated that a set of micro-RNA (miRNA) is significantly down-regulated in anaplastic thyroid carcinomas with respect to normal thyroid tissues and to differentiated ...thyroid carcinomas.
Objective:
The objective was to evaluate the role of two of these down-regulated miRNA, miR-25 and miR-30d, in thyroid carcinogenesis.
Design:
miR-25 and miR-30d expression was restored in the ACT-1, 8505c, and FRO anaplastic thyroid cell lines, and their effects on cell proliferation, migration, and target expression were evaluated.
Results:
We report that miR-25 and miR-30d target the polycomb protein enhancer of zeste 2 (EZH2) that has oncogenic activity and is drastically up-regulated in anaplastic thyroid carcinomas but not in the differentiated ones. Ectopic expression of miR-25 and miR-30d inhibited proliferation and colony formation of anaplastic thyroid carcinoma cells by inducing G2/M-phase cell-cycle arrest. Finally, we found an inverse correlation between the expression of these miRNA and the EZH2 protein levels in anaplastic thyroid carcinomas, suggesting a critical role of these miRNA in regulating EZH2 expression also in vivo.
Conclusion:
The down-regulation of miR-25 and miR-30d could contribute to the process of thyroid cancer progression, leading to the development of anaplastic carcinomas targeting EZH2 mRNA.
Context:
MicroRNA (miRNA) are an important class of regulators of gene expression. Altered miRNA expression has been constantly found in human neoplasias and plays an important role in the process of ...carcinogenesis.
Objective:
The aim of this study was to identify specific miRNA whose expression is altered in GH-secreting pituitary adenomas.
Design:
Using a miRNACHIP microarray, we have analyzed the miRNA expression profile of human GH adenomas vs. normal pituitary gland.
Results:
We report the identification of a set of miRNA, including miR-34b, miR-326, miR-432, miR-548c-3p, miR-570, and miR-603, drastically and constantly down-regulated in GH adenomas. We demonstrate that these miRNA target genes such as high-mobility group A1 (HMGA1), HMGA2, and E2F1, whose overexpression and/or activation plays a critical role in pituitary tumorigenesis. We also show that the enforced expression of the down-regulated miRNA has a negative role on the growth regulation of pituitary adenoma cells. Finally, an inverse correlation is found between the expression of these miRNA and HMGA1 and HMGA2 protein levels in GH adenomas.
Conclusion:
Our study identifies a specific subset of miRNA, whose down-regulation might contribute to pituitary tumorigenesis.
High Mobility Group A1 (HMGA1) is an architectural chromatin protein whose overexpression is a feature of malignant neoplasias with a causal role in cancer initiation and progression. HMGA1 promotes ...tumor growth by several mechanisms, including increase of cell proliferation and survival, impairment of DNA repair and induction of chromosome instability. Autophagy is a self-degradative process that, by providing energy sources and removing damaged organelles and misfolded proteins, allows cell survival under stress conditions. On the other hand, hyper-activated autophagy can lead to non-apoptotic programmed cell death. Autophagy deregulation is a common feature of cancer cells in which has a complex role, showing either an oncogenic or tumor suppressor activity, depending on cellular context and tumor stage. Here, we report that depletion of HMGA1 perturbs autophagy by different mechanisms. HMGA1-knockdown increases autophagosome formation by constraining the activity of the mTOR pathway, a major regulator of autophagy, and transcriptionally upregulating the autophagy-initiating kinase Unc-51-like kinase 1 (ULK1). Consistently, functional experiments demonstrate that HMGA1 binds ULK1 promoter region and negatively regulates its transcription. On the other hand, the increase in autophagosomes is not associated to a proportionate increase in their maturation. Overall, the effects of HMGA1 depletion on autophagy are associated to a decrease in cell proliferation and ultimately impact on cancer cells viability. Importantly, silencing of ULK1 prevents the effects of HMGA1-knockdown on cellular proliferation, viability and autophagic activity, highlighting how these effects are, at least in part, mediated by ULK1. Interestingly, this phenomenon is not restricted to skin cancer cells, as similar results have been observed also in HeLa cells silenced for HMGA1. Taken together, these results clearly indicate HMGA1 as a key regulator of the autophagic pathway in cancer cells, thus suggesting a novel mechanism through which HMGA1 can contribute to cancer progression.
Carcinoma of the thyroid gland is an uncommon cancer, but one of the most frequent malignancies of the endocrine system. Most thyroid cancers are derived from the follicular cells. Follicular ...carcinoma is considered more malignant than papillary thyroid carcinoma (PTC), and anaplastic thyroid cancer (ATC) is one of the most lethal human cancers. Even though several genetic lesions have been already described in human thyroid cancer, particularly in the papillary histotype, the mechanisms underlying the development of these neoplasias are still far from being completely elucidated. Some years ago, several studies were undertaken to analyze the expression of microRNAs (miRNAs or miRs) in thyroid carcinoma to evaluate a possible role of their deregulation in the process of carcinogenesis. These studies showed an aberrant microRNA expression profile that distinguishes unequivocally among PTC, ATC, and normal thyroid tissue. Here, other than summarizing the current findings on microRNA expression in human thyroid carcinomas, we discuss the mechanisms by which microRNA deregulation may play a role in thyroid carcinogenesis, and the possible use of microRNA knowledge in the diagnosis and therapy of thyroid neoplasms.
Recent studies have underlined HMGA protein's key role in the onset of testicular germ cell tumors, where HMGA1 is differently expressed with respect to the state of differentiation, suggesting its ...fine regulation as master regulator in testicular tumorigenesis. Several studies have highlighted that the
transcript is strictly regulated by a set of inhibitory microRNAs. Thus, the aim of this study is to test whether HMGA1 overexpression in human seminomas may be induced by the deregulation of miR-26a and Let-7a-two
-targeting microRNAs.
mRNA and Let-7a and miR-26a levels were measured in a seminoma dataset available in the Cancer Genome Atlas database and confirmed in a subset of seminomas by qRT-PCR and western blot. A TCam-2 seminoma cell line was then transfected with Let-7a and miR-26a and tested for proliferation and motility abilities.
an inverse correlation was found between the expression of miR-26a and Let-7a and
expression levels in seminomas samples, suggesting a critical role of these microRNAs in
levels regulation. Accordingly, functional studies showed that miR-26a and Let-7a inhibited the proliferation, migration and invasion capabilities of the human seminoma derived cell line TCam-2.
these data strongly support that the upregulation of HMGA1 levels occurring in seminoma is-at least in part-due to the downregulation of
-targeting microRNAs.
The high-mobility group A (HMGA) proteins are frequently overexpressed in human malignancies and correlate with the presence of metastases and reduced patient survival. Here, we highlight the main ...studies evidencing a critical role of HMGA in chemoresistance, mainly by activating Akt signaling, impairing p53 activity, and regulating the expression of microRNAs that target genes involved in the susceptibility of cancer cells to antineoplastic agents. Therefore, these studies account for the association of HMGA overexpression with patient poor outcome, indicating the impairment of HMGA as a fascinating perspective for effectively improving cancer therapy.
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