Splicing Genomics Events in Cervical Cancer: Insights for Phenotypic Stratification and Biomarker Potency

Gynaecological cancers are attributed to the second most diagnosed cancers in women after breast cancer. On a global scale, cervical cancer is the fourth most common cancer and the most common cancer in developing countries with rapidly increasing mortality rates. Human papillomavirus (HPV) infection is a major contributor to the disease. HPV infections cause prominent cellular changes including alternative splicing to drive malignant transformation. A fundamental characteristic attributed to cancer is the dysregulation of cellular transcription. Alternative splicing is regulated by several splicing factors and molecular changes in these factors lead to cancer mechanisms such as tumour development and progression and drug resistance. The serine/arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs) have prominent roles in modulating alternative splicing. Evidence shows molecular alteration and expression levels in these splicing factors in cervical cancer. Furthermore, aberrant splicing events in cancer-related genes lead to chemo- and radioresistance. Identifying clinically relevant modifications in alternative splicing events and splicing variants, in cervical cancer, as potential biomarkers for their role in cancer progression and therapy resistance is scrutinised. This review will focus on the molecular mechanisms underlying the aberrant splicing events in cervical cancer that may serve as potential biomarkers for diagnosis, prognosis, and novel drug targets.

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Galectin-3: A factotum in carcinogenesis bestowing an archery for prevention

Tumor Biology ◽

10.3233/tub-200051 ◽

2021 ◽

Vol 43 (1) ◽

pp. 77-96

Author(s):

T. Jeethy Ram ◽

Asha Lekshmi ◽

Thara Somanathan ◽

K. Sujathan

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Cellular Level ◽

Clinical Samples ◽

Innovative Strategy ◽

Mesenchymal Transition ◽

Galectin 3

Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention.

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Transformer 2β Regulates the Alternative Splicing of Cell Cycle Regulator Genes to Promote Ovarian Cancer Cell Progression

10.21203/rs.3.rs-853170/v1 ◽

2021 ◽

Author(s):

Peiying Fu ◽

Ting Zhou ◽

Dong Chen ◽

ShiXuan Wang ◽

Ronghua Liu

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Alternative Splicing ◽

Cancer Progression ◽

Poor Prognosis ◽

Molecular Mechanisms ◽

Rna Binding ◽

Rna Binding Proteins ◽

Expression Level

Abstract Background: Late-stage ovarian cancer (OV) has a poor prognosis and a high metastasis rate, but the underlying molecular mechanism is ambiguous. RNA binding proteins (RBPs) play important roles in posttranscriptional regulation in the contexts of neoplasia and tumor metastasis. Results: In this study, we explored the molecular functions of a canonical RBP, TRA2B, in cancer cells. TRA2B knockdown in HeLa cells and whole-transcriptome sequencing (RNA-seq) experiments revealed that the TRA2B-regulated alternative splicing (AS) profile was tightly associated with the mitotic cell cycle, apoptosis, and several cancer pathways. Moreover, hundreds of genes were regulated by TRA2B at the expression level, and their functions were enriched in cell proliferation, cell adhesion and angiogenesis, which are related to cancer progression. We also observed that AS regulation and expression regulation occurred independently by integrating the alternatively spliced and differentially expressed genes. We then explored and validated the carcinogenic functions of TRA2B by knocking down its expression in OV cells. In vivo, a high expression level of TRA2B was associated with a poor prognosis in OV patients. Conclusions: We demonstrated the important roles of TRA2B in ovarian neoplasia and OV progression and identified the underlying molecular mechanisms, facilitating the targeted treatment of OV in the future.

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An Arabidopsis long noncoding RNA modulates the transcriptome through interactions with a network of splicing factors

10.1101/2020.01.03.894055 ◽

2020 ◽

Author(s):

Richard Rigo ◽

Jérémie Bazin ◽

Natali Romero-Barrios ◽

Michaël Moison ◽

Leandro Lucero ◽

...

Keyword(s):

Alternative Splicing ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Root Formation ◽

Noncoding Rnas ◽

Dynamic Network ◽

Splicing Factors ◽

Genome Wide ◽

A Minor ◽

Conserved Core

ABSTRACTAlternative splicing (AS) is a major source of transcriptome and proteome diversity in higher organisms. Long noncoding RNAs (lncRNAs) have emerged as regulators of AS through a range of molecular mechanisms. In Arabidopsis thaliana, the AS regulators NSRa and b, which affect auxin-driven lateral root formation, can interact with the ALTERNATIVE SPLICING COMPETITOR (ASCO) lncRNA. Here, we analyzed the effect of the knockdown and overexpression of ASCO at genome-wide level and found a high number of deregulated and differentially spliced genes, related to flagellin responses and biotic stress. In agreement, roots from ASCO-knocked down plants are more sensitive to flagellin. Surprisingly, only a minor subset of genes overlapped with the AS defects of the nsra/b double mutant. Using biotin-labelled oligonucleotides for RNA-mediated ribonucleoprotein purification, we found that ASCO binds to the highly conserved core spliceosome component PRP8a. ASCO deregulation impairs the recognition of specific flagellin-related transcripts by PRP8a and SmD1b, another spliceosome component, suggesting that ASCO function regulates AS through the interaction with multiple splicing factors. Hence, lncRNAs may interact in a dynamic network with many splicing factors to modulate transcriptome reprogramming in eukaryotes.

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Impact of Alternative Splicing Variants on Liver Cancer Biology

Cancers ◽

10.3390/cancers14010018 ◽

2021 ◽

Vol 14 (1) ◽

pp. 18

Author(s):

Jose J. G. Marin ◽

Maria Reviejo ◽

Meraris Soto ◽

Elisa Lozano ◽

Maitane Asensio ◽

...

Keyword(s):

Alternative Splicing ◽

Cancer Cells ◽

Cancer Biology ◽

Survival Rates ◽

Splicing Factors ◽

Aberrant Splicing ◽

Splicing Variants ◽

Mrna Maturation ◽

Available Information ◽

The Impact

The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.

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Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer

Cells ◽

10.3390/cells9061481 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1481

Author(s):

Chenghui Zhou ◽

Ningbo Fan ◽

Fanyu Liu ◽

Nan Fang ◽

Patrick S. Plum ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Resistance Mechanism ◽

Therapy Resistance ◽

Metabolic Reprogramming ◽

Current Evidence ◽

Mesenchymal Transition ◽

Therapeutic Implications

Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer.

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Identification of Alternative Splicing Factors Involved in Prostate Cancer Progression

10.21236/ada420782 ◽

2003 ◽

Author(s):

Russ P. Carstens

Keyword(s):

Prostate Cancer ◽

Alternative Splicing ◽

Cancer Progression ◽

Splicing Factors ◽

Prostate Cancer Progression

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Metastatic suppression by DOC2B is mediated by inhibition of epithelial-mesenchymal transition and induction of senescence

Cell Biology and Toxicology ◽

10.1007/s10565-021-09598-w ◽

2021 ◽

Author(s):

Samatha Bhat ◽

Divya Adiga ◽

Vaibhav Shukla ◽

Kanive Parashiva Guruprasad ◽

Shama Prasada Kabekkodu ◽

...

Keyword(s):

Cervical Cancer ◽

Tumor Growth ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Vesicle Trafficking ◽

Critical Role ◽

Anoikis Resistance ◽

Mesenchymal Transition ◽

Intracellular Vesicle

AbstractSenescence induction and epithelial-mesenchymal transition (EMT) events are the opposite sides of the spectrum of cancer phenotypes. The key molecules involved in these processes may get influenced or altered by genetic and epigenetic changes during tumor progression. Double C2-like domain beta (DOC2B), an intracellular vesicle trafficking protein of the double C2 protein family, plays a critical role in exocytosis, neurotransmitter release, and intracellular vesicle trafficking. DOC2B is repressed by DNA promoter hypermethylation and functions as a tumor growth regulator in cervical cancer. To date, the molecular mechanisms of DOC2B in cervical cancer progression and metastasis is elusive. Herein, the biological functions and molecular mechanisms regulated by DOC2B and its impact on senescence and EMT are described. DOC2B inhibition promotes proliferation, growth, and migration by relieving G0/G1-S arrest, actin remodeling, and anoikis resistance in Cal27 cells. It enhanced tumor growth and liver metastasis in nude mice with the concomitant increase in metastasis-associated CD55 and CD61 expression. Inhibition of EMT and promotion of senescence by DOC2B is a calcium-dependent process and accompanied by calcium-mediated interaction between DOC2B and CDH1. In addition, we have identified several EMT and senescence regulators as targets of DOC2B. We show that DOC2B may act as a metastatic suppressor by inhibiting EMT through induction of senescence via DOC2B-calcium-EMT-senescence axis. Graphical abstract

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Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL

Pharmaceutics ◽

10.3390/pharmaceutics13071062 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1062

Author(s):

Adriana G. Quiroz-Reyes ◽

Paulina Delgado-Gonzalez ◽

Jose Francisco Islas ◽

Juan Luis Delgado Gallegos ◽

Javier Humberto Martínez Martínez Garza ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Invasion Pathways ◽

Trail Resistance ◽

Novel Strategy ◽

Cancer Remission

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.

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Alternative splicing regulation of cell cycle genes by SPF45/SR140/CHERP complex controls cell proliferation

RNA ◽

10.1261/rna.078935.121 ◽

2021 ◽

pp. rna.078935.121

Author(s):

Elena Martin ◽

Claudia Vivori ◽

Malgorzata Rogalska ◽

Jorge Herrero ◽

Juan Valcarcel

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Alternative Splicing ◽

Cell Cycle Progression ◽

Molecular Mechanisms ◽

Splicing Factors ◽

Splicing Regulation ◽

Cancer Cell Proliferation ◽

Cycle Progression ◽

Regulation Of Cell Cycle

The regulation of pre-mRNA processing has important consequences for cell division and the control of cancer cell proliferation but the underlying molecular mechanisms remain poorly understood. We report that three splicing factors, SPF45, SR140 and CHERP form a tight physical and functionally coherent complex that regulates a variety of alternative splicing events, frequently by repressing short exons flanked by suboptimal 3' splice sites. These comprise alternative exons embedded in genes with important functions in cell cycle progression, including the G2/M key regulator FOXM1 and the spindle regulator SPDL1. Knockdown of either of the three factors leads to G2/M arrest and to enhanced apoptosis in HeLa cells. Promoting the changes in FOXM1 or SPDL1 splicing induced by SPF45/SR140/CHERP knockdown partially recapitulate the effects on cell growth, arguing that the complex orchestrates a program of alternative splicing necessary for efficient cell proliferation.

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Extracellular Vesicles Long Non-Coding RNA AGAP2-AS1 Contributes to Cervical Cancer Cell Proliferation Through Regulating the miR-3064-5p/SIRT1 Axis

Frontiers in Oncology ◽

10.3389/fonc.2021.684477 ◽

2021 ◽

Vol 11 ◽

Author(s):

Min Li ◽

Jing Wang ◽

Hongli Ma ◽

Li Gao ◽

Kunxiang Zhao ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cervical Cancer Cell ◽

Cancer Cell Proliferation ◽

Cervical Cancer Cells

Cervical cancer is one of the most severe and prevalent female malignancies and a global health issue. The molecular mechanisms underlying cervical cancer development are poorly investigated. As a type of extracellular membrane vesicles, EVs from cancer cells are involved in cancer progression by delivering regulatory factors, such as proteins, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). In this study, we identified an innovative function of extracellular vesicle (EV) lncRNA AGAP2-AS1 in regulating cervical cancer cell proliferation. The EVs were isolated from the cervical cancer cells and were observed by transmission electron microscopy (TEM) and were confirmed by analyzing exosome markers. The depletion of AGAP2-AS1 by siRNA significantly reduced its expression in the exosomes from cervical cancer and in the cervical cancer treated with AGAP2-AS1-knockdown exosomes. The expression of AGAP2-AS1 was elevated in the clinical cervical cancer tissues compared with the adjacent normal tissues. The depletion of EV AGAP2-AS1 reduced cell viabilities and Edu-positive cervical cancer cells, while it enhanced cervical cancer cell apoptosis. Tumorigenicity analysis in nude mice showed that the silencing of EV AGAP2-AS1 attenuated cervical cancer cell growth in vivo. Regarding the mechanism, we identified that AGAP2-AS1 increased SIRT1 expression by sponging miR-3064-5p in cervical cancer cells. The overexpression of SIRT1 or the inhibition of miR-3064-5p reversed EV AGAP2-AS1 depletion-inhibited cancer cell proliferation in vitro. Consequently, we concluded that EV lncRNA AGAP2-AS1 contributed to cervical cancer cell proliferation through regulating the miR-3064-5p/SIRT1 axis. The clinical values of EV lncRNA AGAP2-AS1 and miR-3064-5p deserve to be explored in cervical cancer diagnosis and treatments.

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