Cancers

Research

17 pages, 6364 KiB

Open AccessArticle

Actin-Dependent Mechanism of Tumor Progression Induced by a Dysfunction of p53 Tumor Suppressor

by Natalia Khromova, Maria Vasileva, Vera Dugina, Dmitry Kudlay, Peter Chumakov, Sergei Boichuk and Pavel Kopnin

Cancers 2024, 16(6), 1123; https://doi.org/10.3390/cancers16061123 - 11 Mar 2024

Viewed by 810

Abstract

Cancer cell aggressiveness, marked by actin cytoskeleton reconfiguration critical for metastasis, may result from an imbalanced ratio favoring γ-actin. Dysfunctional p53 emerges as a key regulator of invasiveness and migration in various cancer cells, both in vitro and in vivo. P53 inactivation (via [...] Read more.

Cancer cell aggressiveness, marked by actin cytoskeleton reconfiguration critical for metastasis, may result from an imbalanced ratio favoring γ-actin. Dysfunctional p53 emerges as a key regulator of invasiveness and migration in various cancer cells, both in vitro and in vivo. P53 inactivation (via mutants R175H, R248W, R273H, or TP53 repression) significantly enhanced the migration, invasion, and proliferation of human lung adenocarcinoma A549 cells in vitro and in vivo, facilitating intrapulmonary xenograft metastasis in athymic mice. Conversely, wild-type TP53 (TP53 WT) overexpression in p53-deficient non-small- cell lung cancer (NSCLC) H1299 cells substantially reduced proliferation and migration in vitro, effectively curbing orthotopic tumorigenicity and impeding in vivo metastasis. These alterations in cell motility were closely associated with actin cytoskeleton restructuring, favoring γ-actin, and coincided with ERK1/2-mediated signaling activation, unveiling an innovative regulatory mechanism in malignancy progression. Cancer cell aggressiveness, driven by actin cytoskeleton reorganization and a shift towards γ-actin predominance, may be regulated by p53 dysfunction, thereby providing novel insight into tumor progression mechanisms. Full article

(This article belongs to the Special Issue Genes in Cancer)

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25 pages, 7907 KiB

Open AccessArticle

Targeted DNA Methylation Editing Using an All-in-One System Establishes Paradoxical Activation of EBF3

by Rakesh Banerjee, Priyadarshana Ajithkumar, Nicholas Keestra, Jim Smith, Gregory Gimenez, Euan J. Rodger, Michael R. Eccles, Jisha Antony, Robert J. Weeks and Aniruddha Chatterjee

Cancers 2024, 16(5), 898; https://doi.org/10.3390/cancers16050898 - 23 Feb 2024

Viewed by 1436

Abstract

Cutaneous melanoma is rapidly on the rise globally, surpassing the growth rate of other cancers, with metastasis being the primary cause of death in melanoma patients. Consequently, understanding the mechanisms behind this metastatic process and exploring innovative treatments is of paramount importance. Recent [...] Read more.

Cutaneous melanoma is rapidly on the rise globally, surpassing the growth rate of other cancers, with metastasis being the primary cause of death in melanoma patients. Consequently, understanding the mechanisms behind this metastatic process and exploring innovative treatments is of paramount importance. Recent research has shown promise in unravelling the role of epigenetic factors in melanoma progression to metastasis. While DNA hypermethylation at gene promoters typically suppresses gene expression, we have contributed to establishing the newly understood mechanism of paradoxical activation of genes via DNA methylation, where high methylation coincides with increased gene activity. This mechanism challenges the conventional paradigm that promoter methylation solely silences genes, suggesting that, for specific genes, it might actually activate them. Traditionally, altering DNA methylation in vitro has involved using global demethylating agents, which is insufficient for studying the mechanism and testing the direct consequence of gene methylation changes. To investigate promoter hypermethylation and its association with gene activation, we employed a novel approach utilising a CRISPR-SunTag All-in-one system. Here, we focused on editing the DNA methylation of a specific gene promoter segment (EBF3) in melanoma cells using the All-in-one system. Using bisulfite sequencing and qPCR with RNA-Seq, we successfully demonstrated highly effective methylation and demethylation of the EBF3 promoter, with subsequent gene expression changes, to establish and validate the paradoxical role of DNA methylation. Further, our study provides novel insights into the function of the EBF3 gene, which remains largely unknown. Overall, this study challenges the conventional view of methylation as solely a gene-silencing mechanism and demonstrates a potential function of EBF3 in IFN pathway signalling, potentially uncovering new insights into epigenetic drivers of malignancy and metastasis. Full article

(This article belongs to the Special Issue Genes in Cancer)

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19 pages, 4292 KiB

Open AccessArticle

Development of a Genetically Engineered Mouse Model Recapitulating LKB1 and PTEN Deficiency in Gastric Cancer Pathogenesis

by Kuan-Te Fang, Hsin Hung, Nga Yin Sadonna Lau, Jou-Hsi Chi, Deng-Chyang Wu and Kuang-Hung Cheng

Cancers 2023, 15(24), 5893; https://doi.org/10.3390/cancers15245893 - 18 Dec 2023

Cited by 1 | Viewed by 920

Abstract

The LKB1 and PTEN genes are critical in gastric cancer (G.C.) development. LKB1, a robust tumor suppressor gene, encodes a serine/threonine kinase that directly triggers the activation of AMPK—an integral cellular metabolic kinase. The role of the LKB1 pathway extends to maintaining the [...] Read more.

The LKB1 and PTEN genes are critical in gastric cancer (G.C.) development. LKB1, a robust tumor suppressor gene, encodes a serine/threonine kinase that directly triggers the activation of AMPK—an integral cellular metabolic kinase. The role of the LKB1 pathway extends to maintaining the stability of epithelial junctions by regulating E-cadherin expression. Conversely, PTEN, a frequently mutated tumor suppressor gene in various human cancers, emerges as a pivotal negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. This study is set to leverage the H+/K+ ATPase Cre transgene strain to precisely target Cre recombinase expression at parietal cells within the stomach. This strategic maneuver seeks to selectively nullify the functions of both LKB1 and PTEN in a manner specific to the stomach, thereby instigating the development of G.C. in a fashion akin to human gastric adenocarcinoma. Moreover, this study endeavors to dissect the intricate ways in which these alterations contribute to the histopathologic advancement of gastric tumors, their potential for invasiveness and metastasis, their angiogenesis, and the evolving tumor stromal microenvironment. Our results show that conditional deletion of PTEN and LKB1 provides an ideal cancer microenvironment for G.C. tumorigenesis by promoting cancer cell proliferation, angiogenesis, and metastasis. Full article

(This article belongs to the Special Issue Genes in Cancer)

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18 pages, 4943 KiB

Open AccessArticle

An Image-Based Identification of Aggressive Breast Cancer Circulating Tumor Cell Subtypes

by Mohamed Kamal, Yiru Jess Wang, Sarai Plummer, Amber Dickerson and Min Yu

Cancers 2023, 15(10), 2669; https://doi.org/10.3390/cancers15102669 - 9 May 2023

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Abstract

Using previously established CTC lines from breast cancer patients, we identified different morphometric subgroups of CTCs with one of them having the highest tumorigenic potential in vivo despite the slowest cell proliferation in vitro. This subgroup represents 32% of all cells and contains [...] Read more.

Using previously established CTC lines from breast cancer patients, we identified different morphometric subgroups of CTCs with one of them having the highest tumorigenic potential in vivo despite the slowest cell proliferation in vitro. This subgroup represents 32% of all cells and contains cells with small cell volume, large nucleus to cell, dense nuclear areas to the nucleus, mitochondria to cell volume ratios and rough texture of cell membrane and termed “Small cell, Large mitochondria, Rough membrane” (SLR). RNA-seq analyses showed that the SLR group is enriched in pathways and cellular processes related to DNA replication, DNA repair and metabolism. SLR upregulated genes are associated with poor survival in patients with ER+ breast cancer based on the KM Plotter database. The high tumorigenic potential, slow proliferation, and enriched DNA replication/repair pathways suggest that the SLR subtype is associated with stemness properties. Our new findings provide a simple image-based identification of CTC subpopulations with elevated aggressiveness, which is expected to provide a more accurate prediction of patient survival and therapy response than total CTC numbers. The detection of morphometric and transcriptomic profiles related to the SLR subgroup of CTCs also opens opportunities for potential targeted cancer treatment. Full article

(This article belongs to the Special Issue Genes in Cancer)

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16 pages, 2262 KiB

Open AccessArticle

Comprehensive Analysis of Gene Expression Profiling to Explore Predictive Markers for Eradication Therapy Efficacy against Helicobacter pylori-Negative Gastric MALT Lymphoma

by Hidehiko Takigawa, Ryo Yuge, Ryo Miyamoto, Rina Otani, Hiroki Kadota, Yuichi Hiyama, Ryohei Hayashi, Yuji Urabe, Kazuhiro Sentani, Naohide Oue, Yasuhiko Kitadai, Shiro Oka and Shinji Tanaka

Cancers 2023, 15(4), 1206; https://doi.org/10.3390/cancers15041206 - 14 Feb 2023

Viewed by 2044

Abstract

Although radiotherapy is the standard treatment for Helicobacter pylori (Hp)-negative gastric mucosa-associated lymphoid tissue (MALT) lymphoma, eradication therapy using antibiotics and an acid secretion suppressor can sometimes induce complete remission. We explored predictive markers for the response to eradication therapy for gastric MALT [...] Read more.

Although radiotherapy is the standard treatment for Helicobacter pylori (Hp)-negative gastric mucosa-associated lymphoid tissue (MALT) lymphoma, eradication therapy using antibiotics and an acid secretion suppressor can sometimes induce complete remission. We explored predictive markers for the response to eradication therapy for gastric MALT lymphoma that were negative for both API2-MALT1 and Hp infection using comprehensive RNA sequence analysis. Among 164 gastric MALT lymphoma patients who underwent eradication therapy as primary treatment, 36 were negative for both the API2-MALT1 fusion gene and Hp infection. Based on eradication therapy efficacy, two groups were established: complete response (CR) and no change (NC). The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that cancer-related genes and infection-related genes were highly expressed in the NC and CR groups, respectively. Based on this finding and transcription factor, gene ontology enrichment, and protein–protein interaction analyses, we selected 16 candidate genes for predicting eradication therapy efficacy. Real-time PCR validation in 36 Hp-negative patients showed significantly higher expression of olfactomedin-4 (OLFM4) and the Nanog homeobox (NANOG) in the CR and NC groups, respectively. OLFM4 and NANOG could be positive and negative predictive markers, respectively, for eradication therapy efficacy against gastric MALT lymphoma that is negative for both API2-MALT1 and Hp infection. Full article

(This article belongs to the Special Issue Genes in Cancer)

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Review

Jump to: Research, Other

17 pages, 1668 KiB

Open AccessReview

Therapeutic Strategies for RB1-Deficient Cancers: Intersecting Gene Regulation and Targeted Therapy

by Mo-Fan Huang, Yuan-Xin Wang, Yu-Ting Chou and Dung-Fang Lee

Cancers 2024, 16(8), 1558; https://doi.org/10.3390/cancers16081558 - 19 Apr 2024

Viewed by 726

Abstract

The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. [...] Read more.

The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. RB1′s canonical function in cell cycle control and DNA repair mechanisms underscores its significance in restraining aberrant cell growth and maintaining genomic stability. Understanding the complex interplay between RB1 and cellular pathways is beneficial to fully elucidate its tumor-suppressive role across different cancer types and for therapeutic development. As a result, investigating vulnerabilities arising from RB1 deletion-associated mechanisms offers promising avenues for targeted therapy. Recently, several findings highlighted multiple methods as a promising strategy for combating tumor growth driven by RB1 loss, offering potential clinical benefits in various cancer types. This review summarizes the multifaceted role of RB1 in cancer biology and its implications for targeted therapy. Full article

(This article belongs to the Special Issue Genes in Cancer)

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17 pages, 1430 KiB

Open AccessReview

SNP-Target Genes Interaction Perturbing the Cancer Risk in the Post-GWAS

by Wenmin Yang, Te Zhang, Xuming Song, Gaochao Dong, Lin Xu and Feng Jiang

Cancers 2022, 14(22), 5636; https://doi.org/10.3390/cancers14225636 - 17 Nov 2022

Cited by 9 | Viewed by 2518

Abstract

Cancer ranks as the second leading cause of death worldwide, and, being a genetic disease, it is highly heritable. Over the past few decades, genome-wide association studies (GWAS) have identified many risk-associated loci harboring hundreds of single nucleotide polymorphisms (SNPs). Some of these [...] Read more.

Cancer ranks as the second leading cause of death worldwide, and, being a genetic disease, it is highly heritable. Over the past few decades, genome-wide association studies (GWAS) have identified many risk-associated loci harboring hundreds of single nucleotide polymorphisms (SNPs). Some of these cancer-associated SNPs have been revealed as causal, and the functional characterization of the mechanisms underlying the cancer risk association has been illuminated in some instances. In this review, based on the different positions of SNPs and their modes of action, we discuss the mechanisms underlying how SNPs regulate the expression of target genes to consequently affect tumorigenesis and the development of cancer. Full article

(This article belongs to the Special Issue Genes in Cancer)

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Other

Jump to: Research, Review

11 pages, 2317 KiB

Open AccessSystematic Review

Prevalence of Germline BRCA1/2 Variants in Ashkenazi and Non-Ashkenazi Prostate Cancer Populations: A Systematic Review and Meta-Analysis

by Antonio Cioffi, Ottavio De Cobelli, Paolo Veronesi, Carlo La Vecchia, Patrick Maisonneuve and Giovanni Corso

Cancers 2023, 15(1), 306; https://doi.org/10.3390/cancers15010306 - 2 Jan 2023

Cited by 1 | Viewed by 1765

Abstract

Background and aims: International guidelines recommend testing BRCA2 in men with prostate cancer, due to the presence of a strong association with this gene. Some ethnicities present disparities in genetic distribution for the relation with specific founder variants. Ashkenazi Jewish people are, importantly, [...] Read more.

Background and aims: International guidelines recommend testing BRCA2 in men with prostate cancer, due to the presence of a strong association with this gene. Some ethnicities present disparities in genetic distribution for the relation with specific founder variants. Ashkenazi Jewish people are, importantly, at high risk of breast cancer for their inherited cluster with germline BRCA1/2 variants. However, in Ashkenazi men with prostate cancer, the prevalence of BRCA1 and/or BRCA2 is not well defined. We assessed the frequency of these variants in Ashkenazi vs. non-Ashkenazi men with prostate cancer. Materials and Methods: In accord with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, we revised all germline BRCA variants reported in MEDLINE from 1996 to 2021 in Ashkenazi and non-Ashkenazi men with prostate cancer. Results: Thirty-five original studies were selected for the analysis. Among populations from Israel and North America, Ashkenazi Jewish men presented higher prevalence of BRCA1 variants [0.9% (0.4–1.5) vs. 0.5% (0.2–1.1), p = 0.09] and a lower prevalence of BRCA2 variants [1.5% (1.1–2.0) vs. 3.5% (1.7–5.9), p = 0.08] in comparison to the non-Ashkenazi population. Conclusions: Since germline BRCA1 variants are more prevalent and BRCA2 variants are less prevalent in PCa patients of Ashkenazi Jewish ethnicity in comparison to non-Ashkenazi patients, prostate cancer genetic screening in Ashkenazi men should not be restricted to the BRCA2 gene. Full article

(This article belongs to the Special Issue Genes in Cancer)

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