Role of RUNX2 in Melanoma: A New Player in Tumor Progression and Resistance to Therapy

Mapping Intimacies ◽

10.5772/intechopen.97105 ◽

2021 ◽

Author(s):

Rachael Pulica ◽

Cohen Solal Karine ◽

Ahmed Lasfar

Keyword(s):

Osteoblast Differentiation ◽

Skeletal Development ◽

Critical Role ◽

Invasion And Metastasis ◽

Braf Mutations ◽

Mesenchymal Progenitors ◽

Oncogenic Pathways ◽

Cancer Types ◽

Braf Mutant

RUNX2, a transcription factor, initially known for its indispensable role in skeletal development. RUNX2 is essential for osteoblast differentiation and the maintain of the osteocyte balance. RUNX2 acts directly on osteoblasts via Fgf pathway or on mesenchymal progenitors through Hedgehog, Wnt, Pthlh and DLX5. Currently, many reports point its critical role in the progression and metastasis of several cancer types. RUNX2 is involved in EMT process, invasion and metastasis through the modulation of important oncogenic pathways, including Wnt, FAK/PTK and AKT. In melanoma, RUNX2 is a key player in mediating intrinsic RTK-associated pro-oncogenic properties. We have showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL, in melanoma cells rendered resistant to BRAF mutant inhibitors. Approximately half of melanomas carry BRAF mutations which enhance tumor invasion and metastasis. In this chapter, we describe the potential mechanisms, leading to the upregulation of RUNX2 in melanoma with BRAF mutations. We also highlight the critical role of PI3K/AKT in the expression and activation of RUNX2, and its consequences on the regulation of many critical factors, controlling cancer invasion and metastasis.

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Critical role of the extracellular signal–regulated kinase–MAPK pathway in osteoblast differentiation and skeletal development

Journal of Experimental Medicine ◽

10.1084/jem2043oia6 ◽

2007 ◽

Vol 204 (3) ◽

pp. i6-i6

Author(s):

Chunxi Ge ◽

Guozhi Xiao ◽

Di Jiang ◽

Renny T. Franceschi

Keyword(s):

Osteoblast Differentiation ◽

Mapk Pathway ◽

Skeletal Development ◽

Critical Role ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal

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The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling

Nature Communications ◽

10.1038/s41467-021-24631-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Eui Jung Moon ◽

Stephano S. Mello ◽

Caiyun G. Li ◽

Jen-Tsan Chi ◽

Kaushik Thakkar ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Invasion ◽

Critical Role ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

Invasion And Metastasis ◽

Stat3 Signaling ◽

Inducible Genes ◽

Transcriptional Target

AbstractHypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.

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The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review

Cancers ◽

10.3390/cancers13163949 ◽

2021 ◽

Vol 13 (16) ◽

pp. 3949

Author(s):

Federica Rascio ◽

Federica Spadaccino ◽

Maria Teresa Rocchetti ◽

Giuseppe Castellano ◽

Giovanni Stallone ◽

...

Keyword(s):

Drug Resistance ◽

Akt Pathway ◽

Invasion And Metastasis ◽

Pathogenic Role ◽

Multiple Cancer ◽

Downstream Target ◽

Cancer Types ◽

Multi Level ◽

Survival Mechanisms

The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available.

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The Role of WAVE2 Signaling in Cancer

Biomedicines ◽

10.3390/biomedicines9091217 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1217

Author(s):

Priyanka Shailendra Rana ◽

Akram Alkrekshi ◽

Wei Wang ◽

Vesna Markovic ◽

Khalid Sossey-Alaoui

Keyword(s):

Actin Cytoskeleton ◽

Cancer Cell ◽

Cell Invasion ◽

Critical Role ◽

Therapeutic Strategies ◽

Small Gtpases ◽

Cancer Cell Invasion ◽

Invasion And Metastasis ◽

Regulatory Complex

The Wiskott–Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE)—WAVE1, WAVE2 and WAVE3 regulate rapid reorganization of cortical actin filaments and have been shown to form a key link between small GTPases and the actin cytoskeleton. Upon receiving upstream signals from Rho-family GTPases, the WASP and WAVE family proteins play a significant role in polymerization of actin cytoskeleton through activation of actin-related protein 2/3 complex (Arp2/3). The Arp2/3 complex, once activated, forms actin-based membrane protrusions essential for cell migration and cancer cell invasion. Thus, by activation of Arp2/3 complex, the WAVE and WASP family proteins, as part of the WAVE regulatory complex (WRC), have been shown to play a critical role in cancer cell invasion and metastasis, drawing significant research interest over recent years. Several studies have highlighted the potential for targeting the genes encoding either part of or a complete protein from the WASP/WAVE family as therapeutic strategies for preventing the invasion and metastasis of cancer cells. WAVE2 is well documented to be associated with the pathogenesis of several human cancers, including lung, liver, pancreatic, prostate, colorectal and breast cancer, as well as other hematologic malignancies. This review focuses mainly on the role of WAVE2 in the development, invasion and metastasis of different types of cancer. This review also summarizes the molecular mechanisms that regulate the activity of WAVE2, as well as those oncogenic pathways that are regulated by WAVE2 to promote the cancer phenotype. Finally, we discuss potential therapeutic strategies that target WAVE2 or the WAVE regulatory complex, aimed at preventing or inhibiting cancer invasion and metastasis.

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SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

Cancers ◽

10.3390/cancers12010142 ◽

2020 ◽

Vol 12 (1) ◽

pp. 142 ◽

Cited By ~ 4

Author(s):

Cinzia Bottino ◽

Alessia Peserico ◽

Cristiano Simone ◽

Giuseppina Caretti

Keyword(s):

Signaling Pathways ◽

Cancer Progression ◽

Transcriptional Response ◽

Migration And Invasion ◽

Transcriptional Reprogramming ◽

Oncogenic Pathways ◽

Tumor Transformation ◽

Cancer Types ◽

Oncogenic Driver

SMYD3 is a member of the SMYD lysine methylase family and plays an important role in the methylation of various histone and non-histone targets. Aberrant SMYD3 expression contributes to carcinogenesis and SMYD3 upregulation was proposed as a prognostic marker in various solid cancers. Here we summarize SMYD3-mediated regulatory mechanisms, which are implicated in the pathophysiology of cancer, as drivers of distinct oncogenic pathways. We describe SMYD3-dependent mechanisms affecting cancer progression, highlighting SMYD3 interplay with proteins and RNAs involved in the regulation of cancer cell proliferation, migration and invasion. We also address the effectiveness and mechanisms of action for the currently available SMYD3 inhibitors. The findings analyzed herein demonstrate that a complex network of SMYD3-mediated cytoplasmic and nuclear interactions promote oncogenesis across different cancer types. These evidences depict SMYD3 as a modulator of the transcriptional response and of key signaling pathways, orchestrating multiple oncogenic inputs and ultimately, promoting transcriptional reprogramming and tumor transformation. Further insights into the oncogenic role of SMYD3 and its targeting of different synergistic oncogenic signals may be beneficial for effective cancer treatment.

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A Murine Model for Human ECO Syndrome Reveals a Critical Role of Intestinal Cell Kinase in Skeletal Development

Calcified Tissue International ◽

10.1007/s00223-017-0355-3 ◽

2017 ◽

Vol 102 (3) ◽

pp. 348-357 ◽

Cited By ~ 6

Author(s):

Mengmeng Ding ◽

Li Jin ◽

Lin Xie ◽

So Hyun Park ◽

Yixin Tong ◽

...

Keyword(s):

Murine Model ◽

Skeletal Development ◽

Critical Role ◽

Intestinal Cell ◽

Intestinal Cell Kinase

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Landscape Profiling Analysis of DPP4 in Malignancies: Therapeutic Implication for Tumor Patients With Coronavirus Disease 2019

Frontiers in Oncology ◽

10.3389/fonc.2021.624899 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lingling Shu ◽

Yang Liu ◽

Jinyuan Li ◽

Xiaoping Wu ◽

Yang Li ◽

...

Keyword(s):

Cancer Patients ◽

Critical Role ◽

Therapeutic Effects ◽

Strong Correlations ◽

Tumor Patients ◽

Dipeptidyl Peptidase 4 ◽

Specific Tumor ◽

Cancer Types ◽

Profiling Analysis

Severe coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by pneumonia, lymphopenia, and cytokine storms. Patients with underlying conditions, and especially cancer patients with impaired immunity, are particularly vulnerable to SARS-CoV-2 infection and complications. Although angiotensin converting enzyme II (ACE2) has been identified as a cellular binding receptor for SARS-CoV-2, immunopathological changes in severe cancer patients support the investigation of additional potential receptors such as dipeptidyl peptidase 4 (DPP4), a key immunoregulator. However, a comprehensive profiling analysis of DPP4 in malignancies remains obscure. In this study, using different datasets, we demonstrated the expression of DPP4 in healthy tissues and pan-cancers, showing the risk of different cancer types towards SARS-CoV-2 infection according to DPP4 expression levels. DPP4 expression was positively correlated with infiltrating levels of various immune cells and showed strong correlations with diverse immune marker sets in pan-cancer patients analyzed by Tumor Immune Estimation Resource (TIMER). These findings suggest that increased DPP4 expression in specific cancer patients might account for the high susceptibility to SARS-CoV-2 infection and the induction of cytokine storms. Due to the critical role of DPP4 in immunometabolism, our results indicate that pharmacological inhibition of DPP4 might provide beneficial therapeutic effects for SARS-CoV-2 treatment together with other strategies in specific tumor patients.

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Molecular characterization and clinical relevance of m6A regulators across 33 cancer types

Molecular Cancer ◽

10.1186/s12943-019-1066-3 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 40

Author(s):

Yongsheng Li ◽

Jun Xiao ◽

Jing Bai ◽

Yi Tian ◽

Yinwei Qu ◽

...

Keyword(s):

Clinical Relevance ◽

Critical Role ◽

Genetic Alterations ◽

Biological Processes ◽

Valuable Resource ◽

Multiple Cancer ◽

Molecular Alterations ◽

Prognostic Stratification ◽

Cancer Types

Abstract The methylation of N6 adenosine (m6A) plays a critical role in diverse biological processes. However, knowledge regarding the reconstitution of m6A across cancer types is still lacking. Here, we systematically analyzed the molecular alterations and clinical relevance of m6A regulators across > 10,000 subjects representing 33 cancer types. We found that there are widespread genetic alterations to m6A regulators, and that their expression levels are significantly correlated with the activity of cancer hallmark-related pathways. Moreover, m6A regulators were found to be potentially useful for prognostic stratification, and we identified IGF2BP3 as a potential oncogene across multiple cancer types. Our results provide a valuable resource that will guide both mechanistic and therapeutic analyses of the role of m6A regulators in cancer.

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Interplay between Cellular and Molecular Inflammatory Mediators in Lung Cancer

Mediators of Inflammation ◽

10.1155/2016/3494608 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Mario Orozco-Morales ◽

Giovanny Soca-Chafre ◽

Pedro Barrios-Bernal ◽

Norma Hernández-Pedro ◽

Oscar Arrieta

Keyword(s):

Lung Cancer ◽

Immune Suppression ◽

Critical Role ◽

Inflammatory Cells ◽

T Cell Response ◽

Invasion And Metastasis ◽

Remodeling Of Extracellular Matrix ◽

Tumor Associated Neutrophils

Inflammation is a component of the tumor microenvironment and represents the 7th hallmark of cancer. Chronic inflammation plays a critical role in tumorigenesis. Tumor infiltrating inflammatory cells mediate processes associated with progression, immune suppression, promotion of neoangiogenesis and lymphangiogenesis, remodeling of extracellular matrix, invasion and metastasis, and, lastly, the inhibition of vaccine-induced antitumor T cell response. Accumulating evidence indicates a critical role of myeloid cells in the pathophysiology of human cancers. In contrast to the well-characterized tumor-associated macrophages (TAMs), the significance of granulocytes in cancer has only recently begun to emerge with the characterization of tumor-associated neutrophils (TANs). Recent studies show the importance of CD47 in the interaction with macrophages inhibiting phagocytosis and promoting the migration of neutrophils, increasing inflammation which can lead to recurrence and progression in lung cancer. Currently, therapies are targeted towards blocking CD47 and enhancing macrophage-mediated phagocytosis. However, antibody-based therapies may have adverse effects that limit its use.

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