scholarly journals Emerging Role of isomiRs in Cancer: State of the Art and Recent Advances

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1447
Author(s):  
Veronica Zelli ◽  
Chiara Compagnoni ◽  
Roberta Capelli ◽  
Alessandra Corrente ◽  
Jessica Cornice ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Mirna Biogenesis ◽  
Comprehensive Overview ◽  
Functional Roles ◽  
Sequencing Errors ◽  
Sequencing Technologies ◽  
Physiological Processes ◽  
Cancer Types ◽  
State Of Research

The advent of Next Generation Sequencing technologies brought with it the discovery of several microRNA (miRNA) variants of heterogeneous lengths and/or sequences. Initially ascribed to sequencing errors/artifacts, these isoforms, named isomiRs, are now considered non-canonical variants that originate from physiological processes affecting the canonical miRNA biogenesis. To date, accurate IsomiRs abundance, biological activity, and functions are not completely understood; however, the study of isomiR biology is an area of great interest due to their high frequency in the human miRNome, their putative functions in cooperating with the canonical miRNAs, and potential for exhibiting novel functional roles. The discovery of isomiRs highlighted the complexity of the small RNA transcriptional landscape in several diseases, including cancer. In this field, the study of isomiRs could provide further insights into the miRNA biology and its implication in oncogenesis, possibly providing putative new cancer diagnostic, prognostic, and predictive biomarkers as well. In this review, a comprehensive overview of the state of research on isomiRs in different cancer types, including the most common tumors such as breast cancer, colorectal cancer, melanoma, and prostate cancer, as well as in the less frequent tumors, as for example brain tumors and hematological malignancies, will be summarized and discussed.

scholarly journals Splicing dysregulation as a driver of breast cancer

2018 ◽  
Vol 25 (9) ◽  
pp. R467-R478 ◽  
Author(s):  
Abigail Read ◽  
Rachael Natrajan
Keyword(s):  
Breast Cancer ◽  
High Throughput Sequencing ◽  
Predictive Biomarkers ◽  
Therapy Resistance ◽  
Complete Understanding ◽  
Molecular Abnormalities ◽  
Sequencing Technologies ◽  
Large Repertoire ◽  
Positive Breast Cancer

Breast cancer is known to be a heterogeneous disease driven by a large repertoire of molecular abnormalities, which contribute to its diverse clinical behaviour. Despite the success of targeted therapy approaches for breast cancer patient management, there is still a lack of the molecular understanding of aggressive forms of the disease and clinical management of these patients remains difficult. The advent of high-throughput sequencing technologies has paved the way for a more complete understanding of the molecular make-up of the breast cancer genome. As such, it is becoming apparent that disruption of canonical splicing within breast cancer governs its clinical progression. In this review, we discuss the role of dysregulation of spliceosomal component genes and associated factors in the progression of breast cancer, their role in therapy resistance and the use of quantitative isoform expression as potential prognostic and predictive biomarkers with a particular focus on oestrogen receptor-positive breast cancer.

scholarly journals Biological bases of cancer immunotherapy

2021 ◽  
Vol 23 ◽  
Author(s):  
Maryanne M. Gonzales Carazas ◽  
Joseph A. Pinto ◽  
Fanny L. Casado
Keyword(s):  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Historical Review ◽  
Predictive Biomarkers ◽  
High Variability ◽  
Therapeutic Approaches ◽  
Cancer Treatments ◽  
Cancer Types

Abstract Immunotherapy has changed the landscape of cancer treatment and has significantly improved the outcome of several cancer types including breast, lung, colorectal and prostate. Neoantigen recognition and immune checkpoint inhibitors are nowadays the milestones of different immunotherapeutic regimes; however, high cost, primary and acquired resistance and the high variability of responses make their extensive use difficult. The development of better predictive biomarkers that represent tumour diversity shows promise because there is a significant body of clinical data showing a spectrum of immunotherapeutic responses that might be related back to their specific characteristics. This article makes a conceptual and historical review to summarise the main advances in our understanding of the role of the immune system in cancer, while describing the methodological details that have been successfully implemented on cancer treatments and that may hold the key to improved therapeutic approaches.

A comprehensive overview of PPM1A: From structure to disease

2021 ◽  
pp. 153537022110618
Author(s):  
Mao Li ◽  
Xingfeng Xu ◽  
Yan Su ◽  
Xiaoyun Shao ◽  
Yali Zhou ◽  
...  
Keyword(s):  
Negative Regulator ◽  
Comprehensive Overview ◽  
Physiological Processes ◽  
Stress Response Pathway ◽  
Family Protein ◽  
Wide Range ◽  
Proliferation And Apoptosis ◽  
Insight Into ◽  
Phosphate Groups

PPM1A (magnesium-dependent phosphatase 1 A, also known as PP2Cα) is a member of the Ser/Thr protein phosphatase family. Protein phosphatases catalyze the removal of phosphate groups from proteins via hydrolysis, thus opposing the role of protein kinases. The PP2C family is generally considered a negative regulator in the eukaryotic stress response pathway. PPM1A can bind and dephosphorylate various proteins and is therefore involved in the regulation of a wide range of physiological processes. It plays a crucial role in transcriptional regulation, cell proliferation, and apoptosis and has been suggested to be closely related to the occurrence and development of cancers of the lung, bladder, and breast, amongst others. Moreover, it is closely related to certain autoimmune diseases and neurodegenerative diseases. In this review, we provide an insight into currently available knowledge of PPM1A, including its structure, biological function, involvement in signaling pathways, and association with diseases. Lastly, we discuss whether PPM1A could be targeted for therapy of certain human conditions.

scholarly journals Symbiosis and Dysbiosis of the Human Mycobiome

2021 ◽  
Vol 12 ◽  
Author(s):  
Kirtishri Mishra ◽  
Laura Bukavina ◽  
Mahmoud Ghannoum
Keyword(s):  
Human Health ◽  
Deep Sequencing ◽  
Traditional Culture ◽  
Complex Interplay ◽  
Comprehensive Overview ◽  
Sequencing Technologies ◽  
Medical Domain ◽  
Shed Light

The influence of microbiological species has gained increased visibility and traction in the medical domain with major revelations about the role of bacteria on symbiosis and dysbiosis. A large reason for these revelations can be attributed to advances in deep-sequencing technologies. However, the research on the role of fungi has lagged. With the continued utilization of sequencing technologies in conjunction with traditional culture assays, we have the opportunity to shed light on the complex interplay between the bacteriome and the mycobiome as they relate to human health. In this review, we aim to offer a comprehensive overview of the human mycobiome in healthy and diseased states in a systematic way. The authors hope that the reader will utilize this review as a scaffolding to formulate their understanding of the mycobiome and pursue further research.

scholarly journals The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

2020 ◽  
Vol 140 (5) ◽  
pp. 599-623
Author(s):  
Alexander Bampton ◽  
Lauren M. Gittings ◽  
Pietro Fratta ◽  
Tammaryn Lashley ◽  
Ariana Gatt
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Comprehensive Overview ◽  
Cryptic Exon ◽  
Functional Roles ◽  
Heterogeneous Nuclear Ribonucleoproteins ◽  
Lateral Sclerosis

Abstract Dysregulated RNA metabolism is emerging as a crucially important mechanism underpinning the pathogenesis of frontotemporal dementia (FTD) and the clinically, genetically and pathologically overlapping disorder of amyotrophic lateral sclerosis (ALS). Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins with diverse, multi-functional roles across all aspects of mRNA processing. The role of these proteins in neurodegeneration is far from understood. Here, we review some of the unifying mechanisms by which hnRNPs have been directly or indirectly linked with FTD/ALS pathogenesis, including their incorporation into pathological inclusions and their best-known roles in pre-mRNA splicing regulation. We also discuss the broader functionalities of hnRNPs including their roles in cryptic exon repression, stress granule assembly and in co-ordinating the DNA damage response, which are all emerging pathogenic themes in both diseases. We then present an integrated model that depicts how a broad-ranging network of pathogenic events can arise from declining levels of functional hnRNPs that are inadequately compensated for by autoregulatory means. Finally, we provide a comprehensive overview of the most functionally relevant cellular roles, in the context of FTD/ALS pathogenesis, for hnRNPs A1-U.

scholarly journals Does Subtelomeric Position of COMMD5 Influence Cancer Progression?

2021 ◽  
Vol 11 ◽  
Author(s):  
Carole G. Campion ◽  
Thomas Verissimo ◽  
Suzanne Cossette ◽  
Johanne Tremblay
Keyword(s):  
Tumor Progression ◽  
Cancer Progression ◽  
Genetic Alterations ◽  
Chromosome 8 ◽  
Cell Phenotype ◽  
Physiological Processes ◽  
Potential Link ◽  
Cancer Types ◽  
Oncogenic Function

The COMMD proteins are a family of ten pleiotropic factors which are widely conserved throughout evolution and are involved in the regulation of many cellular and physiological processes. COMMD proteins are mainly expressed in adult tissue and their downregulation has been correlated with tumor progression and poor prognosis in cancer. Among this family, COMMD5 emerged as a versatile modulator of tumor progression. Its expression can range from being downregulated to highly up regulated in a variety of cancer types. Accordingly, two opposing functions could be proposed for COMMD5 in cancer. Our studies supported a role for COMMD5 in the establishment and maintenance of the epithelial cell phenotype, suggesting a tumor suppressor function. However, genetic alterations leading to amplification of COMMD5 proteins have also been observed in various types of cancer, suggesting an oncogenic function. Interestingly, COMMD5 is the only member of this family that is located at the extreme end of chromosome 8, near its telomere. Here, we review some data concerning expression and role of COMMD5 and propose a novel rationale for the potential link between the subtelomeric position of COMMD5 on chromosome 8 and its contrasting functions in cancer.

scholarly journals Role of the Fourth Transmembrane Segment in TRAAK Channel Mechanosensitivity

2018 ◽  
Author(s):  
Mingfeng Zhang ◽  
Fuqiang Yao ◽  
Chengfang Pan ◽  
Zhiqiang Yan
Keyword(s):  
Ion Channels ◽  
Transmembrane Domain ◽  
Mechanical Force ◽  
Dynamic Interactions ◽  
Functional Roles ◽  
Physiological Processes ◽  
Gating Mechanism ◽  
Voltage Gated Ion Channels ◽  
Voltage Sensing Domain

AbstractMechanosensitive ion channels such as Piezo, TRAAK, TRPs and OSCA are important transmembrane proteins that are involved in many physiological processes such as touch, hearing and blood pressure regulation. Unlike ligand-gated channels or voltage-gated ion channels, which have a canonical ligand-binding domain or voltage-sensing domain, the mechanosensitive domain and related gating mechanism remain elusive. TRAAK channels are mechanosensitive channels that convert a physical mechanical force into a flow of potassium ions. The structures of TRAAK channels have been solved, however, the functional roles of the structural domains associated with channel mechanosensitivity remains unclear. Here, we generated a series of chimeric mutations between TRAAK and a non-mechanosensitive silent TWIK-1 K2P channel. We found that the selectivity filter region functions as the major gate of outward rectification and found that lower part of fourth transmembrane domain (M4) is necessary for TRAAK channel mechanosensitivity. We further demonstrated that upper part of M4 can modulate the mechanosensitivity of TRAAK channel. Furthermore, we found that hydrophilic substitutions of W262 and F121 facing each other, and hydrophobic substitutions of Q258 and G124, which are above and below W262 and F121, respectively, greatly increase mechanosensitivity, which suggests that dynamic interactions in the upper part of M4 and PH1 domain are involved in TRAAK channel mechanosensitivity. Interestingly, these gain-of-function mutations are sensitive to cell-poking stimuli, indicating that cell-poking stimuli generate a low membrane mechanical force that opens TRAAK channels. Our results thus showed that fourth transmembrane domain of TRAAK is critical for the gating of TRAAK by mechanical force and suggested that multiple dynamic interactions in the upper part of M4 and PH1 domain are involved in this process.

scholarly journals Regulation of let-7 microRNAs by a two-step turnover pathway is of critical pathophysiological significance in humans

2021 ◽  
Author(s):  
Rohit Nalawade ◽  
Tamoghna Chowdhury ◽  
Saibal Chatterjee
Keyword(s):  
Cellular Proliferation ◽  
Human Cancer ◽  
Metastatic Potential ◽  
Mirna Biogenesis ◽  
Human Cancer Cell Lines ◽  
Physiological Processes ◽  
Consistent Manner ◽  
Transcriptomics Data ◽  
And Function

MicroRNAs (miRNAs) are critical regulators of diverse developmental and physiological processes in animals, and their dysregulation has been linked to various disorders and diseases. Not only multiple regulatory mechanisms acting at different levels of human miRNA biogenesis determine miRNA abundance and function, but a few recently identified factors by facilitating miRNA turnover also make critical contributions. We demonstrate that the ribonuclease XRN2, whose worm ortholog had previously been shown to actively degrade let-7 family of miRNAs, can degrade the mature forms of certain let-7 family members in multiple human cancer cell lines, without affecting their precursors. The XRN2-mediated turnover of let-7 has patho-physiological significance as XRN2 depletion results in a reduction in the expression of a number of oncogenes, and diminishes the proliferative and metastatic potential of cancer cells. The clinical relevance of these observations is also verified in tumour transcriptomics data from public RNA-sequencing datasets, where we observe that higher XRN2 mRNA expression is inversely correlated with the levels of mature let-7 miRNAs and associated with poor survival in hepatocellular carcinoma, lung adenocarcinoma, and glioblastoma. We also demonstrate that miRNA turnover is a step-wise process, where a miRNA is released from the grasp of Argonaute before its degradation. This yet unidentified miRNA releasing factor is proteinaceous in nature and its activity is kinetically linked with XRN2-mediated turnover of miRNAs. Our analyses of the patient-derived transcriptomics data also show that XRN2, via its regulation of let-7, affects pathways related to cellular proliferation, development, and signalling in a consistent manner across epithelial and glial cell lineages. Collectively, our studies suggest an important role of XRN2 in regulating cancer physiology through degradation of the let-7 family of miRNAs.

Protein partners of the calcium channel β subunit highlight new cellular functions

2016 ◽  
Vol 473 (13) ◽  
pp. 1831-1844 ◽  
Author(s):  
Mohamad Rima ◽  
Marwa Daghsni ◽  
Ziad Fajloun ◽  
Ridha M'rad ◽  
Juan L. Brusés ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Signalling ◽  
Β Subunit ◽  
Cellular Functions ◽  
Excitable Cells ◽  
Functional Roles ◽  
Physiological Processes ◽  
Protein Partners ◽  
Wide Range

Calcium plays a key role in cell signalling by its intervention in a wide range of physiological processes. Its entry into cells occurs mainly via voltage-gated calcium channels (VGCC), which are found not only in the plasma membrane of excitable cells but also in cells insensitive to electrical signals. VGCC are composed of different subunits, α1, β, α2δ and γ, among which the cytosolic β subunit (Cavβ) controls the trafficking of the channel to the plasma membrane, its regulation and its gating properties. For many years, these were the main functions associated with Cavβ. However, a growing number of proteins have been found to interact with Cavβ, emphasizing the multifunctional role of this versatile protein. Interestingly, some of the newly assigned functions of Cavβ are independent of its role in the regulation of VGCC, and thus further increase its functional roles. Based on the identity of Cavβ protein partners, this review emphasizes the diverse cellular functions of Cavβ and summarizes both past findings as well as recent progress in the understanding of VGCC.

Immunotherapy and potential predictive biomarkers in the treatment of neuroendocrine neoplasia

2020 ◽  
Author(s):  
Guanghui Xu ◽  
Yuhao Wang ◽  
Hushan Zhang ◽  
Xueke She ◽  
Jianjun Yang
Keyword(s):  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
The Body ◽  
Low Grade ◽  
Ablative Therapies ◽  
Cancer Types ◽  
New Treatment ◽  
Well Differentiated

Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. Surgery, locoregional or ablative therapies as well as maintenance treatments are applied in well-differentiated, low-grade NENs, whereas cytotoxic chemotherapy is usually applied in high-grade neuroendocrine carcinomas. However, treatment options for patients with advanced or metastatic NENs are limited. Immunotherapy has provided new treatment approaches for many cancer types, including neuroendocrine tumors, but predictive biomarkers of immune checkpoint inhibitors (ICIs) in the treatment of NENs have not been fully reported. By reviewing the literature and international congress abstracts, we summarize the current knowledge of ICIs, potential predicative biomarkers in the treatment of NENs, implications and efficacy of ICIs as well as biomarkers for NENs of gastroenteropancreatic system, lung NENs and Merkel cell carcinoma in clinical practice.

Sign in / Sign up

Export Citation Format

Share Document