Transcriptomic Analysis of Calcium Remodeling in Colorectal Cancer

Pérez-Riesgo, Enrique; Gutiérrez, Lucía; Ubierna, Daniel; Acedo, Alberto; Moyer, Mary Pat; Núñez, Lucı́a; Alonso, Carlos

doi:10.3390/ijms18050922

Cited by 40 publications

(34 citation statements)

References 42 publications

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“…Ca 2+ is imperative for cellular functions such as intracellular signaling, and IP3R and STIM1 are integral components of the regulatory mechanisms in Ca 2+ signaling within the cell. Remodeling of Ca 2+ homeostasis in CRC contributes to proliferation, invasion, and survival [ 41 , 42 , 43 ]. Based on the studies described above, we hypothesized that increased PDGFRβ induces remodeling of Ca 2+ homeostasis, and, thereby, increases THBS4 secretion.…”

Section: Introductionmentioning

confidence: 99%

Potential Role of PDGFRβ-Associated THBS4 in Colorectal Cancer Development

Kim

Choi

et al. 2020

Cancers

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Colorectal cancer is a significant cause of death since it frequently metastasizes to several organs such as the lung or liver. Tumor development is affected by various factors, including a tumor microenvironment, which may be an essential factor that leads to tumor growth, proliferation, invasion, and metastasis. In the tumor microenvironment, abnormal changes in various growth factors, enzymes, and cytokines can wield a strong influence on cancer. Thrombospondin-4 (THBS4), which is an extracellular matrix protein, also plays essential roles in the tumor microenvironment and mediates angiogenesis by transforming growth factor-β (TGFβ) signaling. Platelet-derived growth factor receptor β (PDGFRβ), which is a receptor tyrosine kinase and is also a downstream signal of TGFβ, is associated with invasion and metastasis in colorectal cancer. We identified that PDGFRβ and THBS4 are overexpressed in tumor tissues of colorectal cancer patients, and that PDGF-D expression increased after TGFβ treatment in the colon cancer cell line DLD-1. TGFβ and PDGF-D increased cellular THBS4 protein levels and secretion but did not increase THBS4 mRNA levels. This response was further confirmed by the inositol 1,4,5-triphosphate receptor (IP3R) and stromal interaction molecule 1 (STIM1) blockade as well as the PDGFRβ blockade. We propose that the PDGFRβ signal leads to a modification of the incomplete form of THBS4 to its complete form through IP3R, STIM1, and Ca2+-signal proteins, which further induces THBS4 secretion. Additionally, we identified that DLD-1 cell-conditioned medium stimulated with PDGF-D promotes adhesion, migration, and proliferation of colon myofibroblast CCD-18co cells, and this effect was intensified in the presence of thrombin. These findings suggest that excessive PDGFRβ signaling due to increased TGFβ and PDGF-D in colorectal tumors leads to over-secretion of THBS4 and proliferative tumor development.

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Section: Introductionmentioning

confidence: 99%

Potential Role of PDGFRβ-Associated THBS4 in Colorectal Cancer Development

Kim

Choi

et al. 2020

Cancers

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“…While analysis of tumour-derived and normal cells of the same tissue origin or neighbouring to the tumour has provided important information [44,53], these controls may not adequately reflect the cell type/genetic status of the cell type of origin. Further inconsistencies are observed on analysis of transformed cells from tumours at different stages and origins as well as whether the original tumour or its metastasis are analysed [54–56].…”

Section: Introductionmentioning

confidence: 99%

Oncogenic KRAS suppresses store-operated Ca 2+ entry and I CRAC through ERK pathway-dependent remodelling of STIM expression in colorectal cancer cell lines

et al. 2018

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The KRAS GTPase plays a fundamental role in transducing signals from plasma membrane growth factor receptors to downstream signalling pathways controlling cell proliferation, survival and migration. Activating KRAS mutations are found in 20% of all cancers and in up to 40% of colorectal cancers, where they contribute to dysregulation of cell processes underlying oncogenic transformation. Multiple KRAS-regulated cell functions are also influenced by changes in intracellular Ca levels that are concurrently modified by receptor signalling pathways. Suppression of intracellular Ca release mechanisms can confer a survival advantage in cancer cells, and changes in Ca entry across the plasma membrane modulate cell migration and proliferation. However, inconsistent remodelling of Ca influx and its signalling role has been reported in studies of transformed cells. To isolate the interaction between altered Ca handling and mutated KRAS in colorectal cancer, we have previously employed isogenic cell line pairs, differing by the presence of an oncogenic KRAS allele (encoding KRAS), and have shown that reduced Ca release from the ER and mitochondrial Ca uptake contributes to the survival advantage conferred by oncogenic KRAS. Here we show in the same cell lines, that Store-Operated Ca Entry (SOCE) and its underlying current, I are under the influence of KRAS. Specifically, deletion of the oncogenic KRAS allele resulted in enhanced STIM1 expression and greater Ca influx. Consistent with the role of KRAS in the activation of the ERK pathway, MEK inhibition in cells with KRAS resulted in increased STIM1 expression. Further, ectopic expression of STIM1 in HCT 116 cells (which express KRAS) rescued SOCE, demonstrating a fundamental role of STIM1 in suppression of Ca entry downstream of KRAS. These results add to the understanding of how ERK controls cancer cell physiology and highlight STIM1 as an important biomarker in cancerogenesis.

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“…As regards secondary tumourigenesis, both increased and decreased VGPC activity could promote the metastatic phenotype by promoting (i) accumulation of mutations and/or (ii) the VGSC activity itself, respectively. In addition, we should note that there is also evidence for major remodeling of Ca 2+ signaling in CRC but this is outside the scope of the present review [159,160].…”

Section: P53 Pathway In Colorectal Cancermentioning

confidence: 87%

Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights

Farooqı

Djamgoz

Siddik

2019

Seminars in Cancer Biology

111

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Colorectal cancer is a multifaceted disease which is therapeutically challenging. Based on insights gleaned from decades of research, it seems clear that deregulation of spatio-temporally controlled signaling pathways play instrumental role in development and progression of colorectal cancer. Highthroughput technologies have helped to develop a sharper and broader understanding of the wide ranging signal transduction cascades which also contribute to development of drug resistance, loss of apoptosis and, ultimately, of metastasis. In this review, we have set the spotlight on role of JAK/STAT, TGF/SMAD, Notch, WNT/β-Catenin, SHH/GLI and p53 pathways in the development and progression of colorectal cancer. We have also highlighted recent reports on TRAIL-mediated pathways and molecularly distinct voltage-gated sodium channels in colorectal cancer. Introduction: Colorectal cancer is the 3 rd commonest cancer and the 2 nd leading cause of cancer-related deaths in the Western world (1). The outlook for disease incidence rates is bleak, reports predict up to a 60% rise in the global burden of CRC in developing countries by 2030 (2). Innovations in disease management are critical. Serine-20, may be less effective at mediating p53-dependent antitumor effects in these specific colorectal cancer patients. To our knowledge, such an investigation has not been reported as yet. Voltage-gated ion (sodium) channel expression in colorectal cancer: The bioelectricity of cancer cells generally differs from normal cells in several different respects [147]. In particular, increasing evidence suggest that a variety of ion channels, including voltage-gated ion channels, play a significant, dynamic role in the pathophysiology of cancer, including CRC [148]. Virtually all types of ion channel are involved, contributing to different components / stages of the cancer process. These include voltage-gated Na + , K +, Ca 2+ and Clchannels, ligand-gated ion channels and 'transient receptor potential' (Trp) channels [148]. Thus, cancer may even be regarded as a 'channelopathy' [148]. Here we focus on ion channels involved in metastasis since this is the main cause of death from cancer including CRC. In this regard, it is that has received the most attention [149]. According to the "Celex Hypothesis", acquisition of metastatic potential in cancer cells involves upregulation of functional voltage-gated Na + channels (VGSCs) activity and concomitant downregulation of outward currents, driven at least in part by voltage-gated K + channels (VGPCs) [150]. Overall, the possible electrical 'excitability' could form the basis of aggressive cancer cell behavior [150]. Membrane and protease genes Wnt signaling MAPK signaling Calcium signaling Membrane remodelling or secretion SCN5A Tumor cell invasion

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Transcriptomic Analysis of Calcium Remodeling in Colorectal Cancer

Cited by 40 publications

References 42 publications

Potential Role of PDGFRβ-Associated THBS4 in Colorectal Cancer Development

Potential Role of PDGFRβ-Associated THBS4 in Colorectal Cancer Development

Oncogenic KRAS suppresses store-operated Ca 2+ entry and I CRAC through ERK pathway-dependent remodelling of STIM expression in colorectal cancer cell lines

Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights

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