Systems-level properties of EGFR/Ras/ERK signalling amplify local signals to generate gene expression plasticity

AbstractThe EGFR/Ras/ERK signalling pathway is a driver of cancer cell proliferation and metastasis in tumours that exhibit high cell-to-cell heterogeneity. While the signalling activity of this pathway is frequently amplified in tumours, it is not understood how the kinetic aspects of its activation in tumours differ from normal cellular signalling. Using live-cell reporters of ERK signalling in the breast cancer progression series HMT-3522, we found that ERK activity in invasive cells is similar in amplitude to isogenic non-malignant cells but is highly dynamic and more disordered, leading to more heterogeneous expression of ERK target genes. Our analysis reveals that this diversification arises from systems-level functions of the pathway, including intracellular amplification of amphiregulin-mediated paracrine signalling and differential kinetic filtering by genes including Fra-1, c-Myc, and Egr1. Our findings establish a mechanism for the generation of non-genetic tumour cell plasticity arising from the specific quantitative properties of a signal transduction pathway.

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δ-Catenin Participates in EGF/AKT/p21Waf Signaling and Induces Prostate Cancer Cell Proliferation and Invasion

International Journal of Molecular Sciences ◽

10.3390/ijms22105306 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5306

Author(s):

Yingjie Shen ◽

Hyoung Jae Lee ◽

Rui Zhou ◽

Hangun Kim ◽

Gen Chen ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Nuclear Accumulation ◽

Cancer Cell Proliferation ◽

Prostate Cancer Progression ◽

Key Factor ◽

Proliferation And Metastasis ◽

First Time ◽

Proliferation And Invasion ◽

Potential Therapeutics

Prostate cancer (PCa) is the second most leading cause of death in males. Our previous studies have demonstrated that δ-catenin plays an important role in prostate cancer progression. However, the molecular mechanism underlying the regulation of δ-catenin has not been fully explored yet. In the present study, we found that δ-catenin could induce phosphorylation of p21Waf and stabilize p21 in the cytoplasm, thus blocking its nuclear accumulation for the first time. We also found that δ-catenin could regulate the interaction between AKT and p21, leading to phosphorylation of p21 at Thr-145 residue. Finally, EGF was found to be a key factor upstream of AKT/δ-catenin/p21 for promoting proliferation and metastasis in prostate cancer. Our findings provide new insights into molecular controls of EGF and the development of potential therapeutics targeting δ-catenin to control prostate cancer progression.

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Exosomal miR-122-5p inhibits tumorigenicity of gastric cancer by downregulating GIT1

The International Journal of Biological Markers ◽

10.1177/1724600821990677 ◽

2021 ◽

Vol 36 (1) ◽

pp. 36-46

Author(s):

Yigang Jiao ◽

Li Zhang ◽

Jun Li ◽

Yuqi He ◽

Xin Zhang ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Gastric Cancer Cell ◽

Cancer Cell Proliferation ◽

Proliferation And Metastasis ◽

Gastric Cancer Cell Proliferation ◽

Gastric Cancer Progression ◽

Cell Proliferation And Metastasis

Background: microRNAs (miRNAs) are non-coding RNAs with important roles in the progression of human cancers, including gastric cancer. Exosomes are extracellular vesicles, which could transfer numerous noncoding RNAs, such as miRNAs. Here, in our study, we intended to investigate the role of exosomal miR-122-5p in gastric cancer progression. Methods: Exosomes were isolated utilizing commercial kit or ultracentrifugation. Biomarkers of exosomes or epithelia-mesenchymal transition (EMT) were monitored by western blot. Expression levels of miR-122-5p and G-protein-coupled receptor kinase interacting protein-1 ( GIT1) were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) or western blot. Cell proliferation and apoptosis were assessed by colony formation assay, methyl thiazolyl tetrazolium assay and flow cytometry. Cell metastasis was evaluated via Transwell assay. The interaction between miR-122-5p and GIT1 was validated by dual-luciferase reporter assay. Furthermore, tumor growth in vivo was detected by xenograft assay. Results: Exosomes were successfully isolated. MiR-122-5p was downregulated in exosomes derived from the serum of gastric cancer patients. Exosomal miR-122-5p could hinder gastric cancer cell proliferation and metastasis in vitro and tumor growth in vivo. Knockdown of GIT1 also inhibited gastric cancer cell proliferation and metastasis. Exosomal miR-122-5p targeted GIT1 to alter cellular behaviors of gastric cancer cells. Conclusion: Exosomal miR-122-5p suppressed gastric cancer progression by targeting GIT1.

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Interleukin-1β and Cancer

Cancers ◽

10.3390/cancers12071791 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1791 ◽

Cited By ~ 2

Author(s):

Cédric Rébé ◽

François Ghiringhelli

Keyword(s):

Cancer Progression ◽

Immune Cells ◽

Gene Polymorphisms ◽

Target Genes ◽

Cell Types ◽

Target Cells ◽

Cancer Cell Proliferation ◽

Cancer Treatments ◽

Anti Cancer ◽

Cellular Context

Within a tumor, IL-1β is produced and secreted by various cell types, such as immune cells, fibroblasts, or cancer cells. The IL1B gene is induced after “priming” of the cells and a second signal is required to allow IL-1β maturation by inflammasome-activated caspase-1. IL-1β is then released and leads to transcription of target genes through its ligation with IL-1R1 on target cells. IL-1β expression and maturation are guided by gene polymorphisms and by the cellular context. In cancer, IL-1β has pleiotropic effects on immune cells, angiogenesis, cancer cell proliferation, migration, and metastasis. Moreover, anti-cancer treatments are able to promote IL-1β production by cancer or immune cells, with opposite effects on cancer progression. This raises the question of whether or not to use IL-1β inhibitors in cancer treatment.

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IGF2BP2 Promotes Cancer Progression by Degrading the RNA Transcript Encoding a v-ATPase Subunit

10.1101/2021.04.01.438101 ◽

2021 ◽

Author(s):

Arash Latifkar ◽

Fangyu Wang ◽

James J. Mullmann ◽

Irma R. Fernandez ◽

Lu Ling ◽

...

Keyword(s):

Cancer Progression ◽

Sirtuin 1 ◽

Cancer Cell Proliferation ◽

Atpase Subunit ◽

Lysosomal Function ◽

Rna Transcripts ◽

Mrna Binding Protein ◽

Acetylation State ◽

Proliferation And Metastasis ◽

Mrna Binding

Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) binds to various RNA transcripts and promotes cancer progression, although little is known regarding its regulation. Here we show IGF2BP2 is a substrate of the deacetylase and tumor suppressor sirtuin 1 (SIRT1) and regulates the expression of the vacuolar ATPase subunit ATP6V1A. SIRT1 down-regulation in aggressive cancers leads to increased acetylation of IGF2BP2 which recruits the XRN2 nuclease to degrade the ATP6V1A transcript, decreasing its expression. This impairs lysosomal function and results in the production of a secretome that enhances cancer cell proliferation and metastasis. These findings describe a previously unrecognized role for IGF2BP2 in the degradation of an mRNA transcript essential for lysosomal function and highlight how its sirtuin-regulated acetylation state can have significant biological and disease consequences.

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Interrupting the FGF19-FGFR4 Axis to Therapeutically Disrupt Cancer Progression

Current Cancer Drug Targets ◽

10.2174/1568009618666180319091731 ◽

2018 ◽

Vol 19 (1) ◽

pp. 17-25 ◽

Cited By ~ 6

Author(s):

Liwei Lang ◽

Austin Y. Shull ◽

Yong Teng

Keyword(s):

Cancer Progression ◽

Therapeutic Strategy ◽

Tumor Development ◽

Vital Role ◽

Signaling Cascades ◽

Cancer Cell Proliferation ◽

Clinical Use ◽

Fibroblast Growth ◽

Apoptosis Resistance ◽

Downstream Signaling

Coordination between the amplification of the fibroblast growth factor FGF19, overexpression of its corresponding receptor FGFR4, and hyperactivation of the downstream transmembrane enzyme β-klotho has been found to play pivotal roles in mediating tumor development and progression. Aberrant FGF19-FGFR4 signaling has been implicated in driving specific tumorigenic events including cancer cell proliferation, apoptosis resistance, and metastasis by activating a myriad of downstream signaling cascades. As an attractive target, several strategies implemented to disrupt the FGF19-FGFR4 axis have been developed in recent years, and FGF19-FGFR4 binding inhibitors are being intensely evaluated for their clinical use in treating FGF19-FGFR4 implicated cancers. Based on the established work, this review aims to detail how the FGF19-FGFR4 signaling pathway plays a vital role in cancer progression and why disrupting communication between FGF19 and FGFR4 serves as a promising therapeutic strategy for disrupting cancer progression.

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Role of MicroRNAs in Colon Cancer Progression and Metastasis

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200825184924 ◽

2020 ◽

Vol 20 ◽

Author(s):

Shruthi Sanjitha Sampath ◽

Sivaramakrishnan Venkatabalsubramanian ◽

Satish Ramalingam

Keyword(s):

Colon Cancer ◽

Cancer Progression ◽

Target Genes ◽

Tumour Progression ◽

Intestinal Barrier ◽

Colon Cancer Progression ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Novel Therapeutic Strategies

: MicroRNAs regulate gene expression at the posttranscriptional level by binding to the mRNA of their target genes. The dysfunction of miRNAs is strongly associated with the inflammation of the colon. Besides, some microRNAs are shown to suppress tumours while others promote tumour progression and metastasis. Inflammatory bowel diseases include Crohn’s disease and Ulcerative colitis which increase the risk factor for inflammation-associated colon cancer. MicroRNAs are shown to be involved in gastrointestinal pathologies, by targeting the transcripts encoding proteins of the intestinal barrier and their regulators that are associated with inflammation and colon cancer. Detection of these microRNAs in the blood, serum, tissues, faecal matter, etc will enable us to use these microRNAs as biomarkers for early detection of the associated malignancies and design novel therapeutic strategies to overcome the same. Information on MicroRNAs can be applied for the development of targeted therapies against inflammation-mediated colon cancer.

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Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Cancers ◽

10.3390/cancers13143465 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3465

Author(s):

Aya Saleh ◽

Ruth Perets

Keyword(s):

Cancer Progression ◽

Target Genes ◽

P53 Protein ◽

Genetic Alterations ◽

Common Mutation ◽

Missense Mutations ◽

P53 Expression ◽

Histologic Subtype ◽

Tp53 Mutations

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.

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Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment

Cancer Cell International ◽

10.1186/s12935-021-02003-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Tiecheng Wang ◽

Jiakang Jin ◽

Chao Qian ◽

Jianan Lou ◽

Jinti Lin ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Immunotherapy ◽

Tumor Immunity ◽

Immune Cells ◽

Target Genes ◽

Target Therapy ◽

Treatment Strategies ◽

Signal Transduction Pathway ◽

Pathway Activation ◽

Immune System Regulation

AbstractAs the essential sexual hormone, estrogen and its receptor has been proved to participate in the regulation of autoimmunity diseases and anti-tumor immunity. The adjustment of tumor immunity is related to the interaction between cancer cells, immune cells and tumor microenvironment, all of which is considered as the potential target in estrogen-induced immune system regulation. However, the specific mechanism of estrogen-induced immunity is poorly understood. Typically, estrogen causes the nuclear localization of estrogen/estrogen receptor complex and alternates the transcription pattern of target genes, leading to the reprogramming of tumor cells and differentiation of immune cells. However, the estrogen-induced non-canonical signal pathway activation is also crucial to the rapid function of estrogen, such as NF-κB, MAPK-ERK, and β-catenin pathway activation, which has not been totally illuminated. So, the investigation of estrogen modulatory mechanisms in these two manners is vital for the tumor immunity and can provide the potential for endocrine hormone targeted cancer immunotherapy. Here, this review summarized the estrogen-induced canonical and non-canonical signal transduction pathway and aimed to focus on the relationship among estrogen and cancer immunity as well as immune-related tumor microenvironment regulation. Results from these preclinical researches elucidated that the estrogen-target therapy has the application prospect of cancer immunotherapy, which requires the further translational research of these treatment strategies.

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UBE2C Drives Human Cervical Cancer Progression and Is Positively Modulated by mTOR

Biomolecules ◽

10.3390/biom11010037 ◽

2020 ◽

Vol 11 (1) ◽

pp. 37

Author(s):

An-Jen Chiang ◽

Chia-Jung Li ◽

Kuan-Hao Tsui ◽

Chung Chang ◽

Yuan-chin Ivan Chang ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Progression ◽

Cancer Staging ◽

Cervical Squamous Cell Carcinoma ◽

Cancer Cell Proliferation ◽

Gynecological Malignancy ◽

In Vivo Experiments ◽

Ubiquitin Conjugating Enzyme

Cervical cancer is a common gynecological malignancy, accounting for 10% of all gynecological cancers. Recently, targeted therapy for cervical cancer has shown unprecedented advantages. Several studies have shown that ubiquitin conjugating enzyme E2 (UBE2C) is highly expressed in a series of tumors, and participates in the progression of these tumors. However, the possible impact of UBE2C on the progression of cervical squamous cell carcinoma (CESC) remains unclear. Here, we carried out tissue microarray analysis of paraffin-embedded tissues from 294 cervical cancer patients with FIGO/TNM cancer staging records. The results indicated that UBE2C was highly expressed in human CESC tissues and its expression was related to the clinical characteristics of CESC patients. Overexpression and knockdown of UBE2C enhanced and reduced cervical cancer cell proliferation, respectively, in vitro. Furthermore, in vivo experiments showed that UBE2C regulated the expression and activity of the mTOR/PI3K/AKT pathway. In summary, we confirmed that UBE2C is involved in the process of CESC and that UBE2C may represent a molecular target for CESC treatment.

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Sulforaphane Inhibits the Expression of Long Noncoding RNA H19 and Its Target APOBEC3G and Thereby Pancreatic Cancer Progression

Cancers ◽

10.3390/cancers13040827 ◽

2021 ◽

Vol 13 (4) ◽

pp. 827

Author(s):

Yiqiao Luo ◽

Bin Yan ◽

Li Liu ◽

Libo Yin ◽

Huihui Ji ◽

...

Keyword(s):

Cancer Progression ◽

Colony Formation ◽

Noncoding Rna ◽

Target Genes ◽

Gene Array ◽

New Drugs ◽

Tumor Promoter ◽

Ductal Adenocarcinoma ◽

Pilot Studies

Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant and the therapeutic options available usually have little impact on survival. Great hope is placed on new therapeutic targets, including long noncoding RNAs (lncRNAs), and on the development of new drugs, based on e.g., broccoli-derived sulforaphane, which meanwhile has shown promise in pilot studies in patients. We examined whether sulforaphane interferes with lncRNA signaling and analyzed five PDAC and two nonmalignant cell lines, patient tissues (n = 30), and online patient data (n = 350). RT-qPCR, Western blotting, MTT, colony formation, transwell and wound healing assays; gene array analysis; bioinformatics; in situ hybridization; immunohistochemistry and xenotransplantation were used. Sulforaphane regulated the expression of all of five examined lncRNAs, but basal expression, biological function and inhibition of H19 were of highest significance. H19 siRNA prevented colony formation, migration, invasion and Smad2 phosphorylation. We identified 103 common sulforaphane- and H19-related target genes and focused to the virus-induced tumor promoter APOBEC3G. APOBEC3G siRNA mimicked the previously observed H19 and sulforaphane effects. In vivo, sulforaphane- or H19 or APOBEC3G siRNAs led to significantly smaller tumor xenografts with reduced expression of Ki67, APOBEC3G and phospho-Smad2. Together, we identified APOBEC3G as H19 target, and both are inhibited by sulforaphane in prevention of PDAC progression.

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