Role of SPARC in the epithelial-mesenchymal transition induced by PTHrP in human colon cancer cells

Carriere, Pedro; Calvo, Natalia; Díaz, María Belén Novoa; López-Moncada, Fernanda; Herrera, Alexander; Torres, María José; Alonso, Exequiel G.; Gandini, Norberto Ariel; Gigola, Graciela; Contreras, Héctor R.; Gentili, Claudia

doi:10.1016/j.mce.2021.111253

Cited by 16 publications

(29 citation statements)

References 55 publications

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“…Although at the end of the trials the differences between the volumes and weights of tumors from untreated and treated animals were not significant, we are sure that if we had continued the assays the size of the tumors in the mice treated with PTHrP would be higher than that observed in control mice. We support this idea because we observed that the continued administration of PTHrP in nude mice xenografts increased the protein levels not only of the mentioned ERK 1/2 MAPK but also of Ki67, which is a marker of CRC cell proliferation, and the following markers: Cyclin D1, CREB/ATF-1, RSK[ 39 , 40 ] and others[ 44 , 45 ], which we will mention in the next sections due to their relation with the tumor-associated angiogenesis and invasion.…”

Section: Pthrp Promotes Cell Cycle Progression Proliferation and Migration Of Crc Cellsmentioning

confidence: 74%

“… Parathyroid hormone-related peptide establishes a communication between colorectal cancer cells and endothelial HMEC cells through molecular factors modulating markers expression and morphological changes associated with cellular programs that promote the invasive phenotype in HCT116 cells. This figure is original for this work and shows results published in Carriere et al [ 45 ]. EMT: Epithelial to mesenchymal transition; PTHrP: Parathyroid hormone-related peptide.…”

Section: Effects Of Pthrp On the Modulation Of Emt Program And Other Events Associated With Invasionmentioning

confidence: 86%

“…As mentioned, during EMT, epithelial cells reduce intercellular adhesion and acquire mesenchymal properties that increase their migration and invasion capacity, recognized characteristics of tumor cells[ 58 ]. The results from the study of the EMT program were incorporated in our work recently accepted for publication[ 45 ]. In this manuscript, we reported that PTHrP modulates the expression of factors and favored morphological changes associated with EMT in the CRC-derived HCT116 cell line (Figure 5 ); we also show that the key molecular mechanisms associated with EMT observed in this cell line in response to PTHrP were not found in the more differentiated and less aggressive Caco-2 cells.…”

Section: Effects Of Pthrp On the Modulation Of Emt Program And Other Events Associated With Invasionmentioning

confidence: 99%

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Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells

Díaz¹,

Carriere²,

Martín³

et al. 2021

WJG

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Colorectal cancer (CRC) remains one of the leading causes of mortality from malignant diseases worldwide. In general terms, CRC presents high heterogeneity due to the influence of different genetic and environmental factors; also, the neoplastic cells are strongly influenced by the extracellular matrix and several surrounding cells, known together as the tumor microenvironment (TME). Bidirectional communication takes place between the tumor and the TME through the release of autocrine and paracrine factors. Parathyroid hormone-related peptide (PTHrP) is a cytokine secreted by a wide variety of tissues and is able to regulate several cellular functions both in physiological as well as in pathological processes. It exerts its effects as a paracrine/autocrine factor, although its mode of action is mainly paracrine. It has been shown that this peptide is expressed by several tumors and that the tumor secretion of PTHrP is responsible for the malignant humoral hypercalcemia. Eight years ago, when our research group started studying PTHrP effects in the experimental models derived from intestinal tumors, the literature available at the time addressing the effects of PTHrP on colorectal tumors was limited, and no articles had been published regarding to the paracrine action of PTHrP in CRC cells. Based on this and on our previous findings regarding the role of PTH in CRC cells, our purpose in recent years has been to explore the role of PTHrP in CRC. We analyzed the behavior of CRC cells treated with exogenous PTHrP, focalizing in the study of the following events: Survival, cell cycle progression and proliferation, migration, chemoresistance, tumor-associated angiogenesis, epithelial to mesenchymal transition program and other events also associated with invasion, such us the induction of cancer stem cells features. This work summarizes the major findings obtained by our investigation group using in vitro and in vivo CRC models that evidence the participation of PTHrP in the acquisition of an aggressive phenotype of CRC cells and the molecular mechanisms involved in these processes. Recently, we found that this cytokine induces this malignant behavior not only by its direct action on these intestinal cells but also through its influence on cells derived from TME, promoting a communication between CRC cells and surrounding cells that contributes to the molecular and morphological changes observed in CRC cells. These investigations establish the basis for our next studies in order to address the clinical applicability of our findings. Recognizing the factors and mechanisms that promote invasion in CRC cells, evasion to the cytotoxic effects of current CRC therapies and thus metastasis is decisive for the identification of new markers with the potential to improve early diagnosis and/or to predict prognosis, to predetermine drug resistance and to provide treatment guidelines that include targeted therapies for this disease.

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Section: Pthrp Promotes Cell Cycle Progression Proliferation and Migration Of Crc Cellsmentioning

confidence: 74%

Section: Effects Of Pthrp On the Modulation Of Emt Program And Other Events Associated With Invasionmentioning

confidence: 86%

Section: Effects Of Pthrp On the Modulation Of Emt Program And Other Events Associated With Invasionmentioning

confidence: 99%

See 1 more Smart Citation

Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells

Díaz¹,

Carriere²,

Martín³

et al. 2021

WJG

Self Cite

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“…All single CTCs and CTC-clusters were also divided into four groups (EMT/Stem cell Group A, B, C and D) by using 11 stem cell related markers ( LGR5 , ALDH2 , CD44 , PROM1 , ABCB2 , SALL4 , KLF4 , MYC , NANOG , SOX2 and POU5F1 ) and seven EMT related markers ( VIM , SPARC , ITGB1 , TFAP4 , ZEB2 , SNAI1 and CDH2 ) ( Figure 3 B). These markers were selected from genes that were previously reported as stem cell or EMT-related genes in colorectal cancer cells [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. EMT/Stem cell Group A had a significantly higher EMT-related gene expression score than other groups, mainly contributed to by VIM , SPARC and ITGB1 , but expressed low stem cell related markers ( Figure S1B,C ).…”

Section: Resultsmentioning

confidence: 99%

Clinical Significance of Circulating Tumor Cell Induced Epithelial-Mesenchymal Transition in Patients with Metastatic Colorectal Cancer by Single-Cell RNA-Sequencing

Kozuka

Battaglin

Jayachandran

et al. 2021

Cancers

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Background: Circulating tumor cells (CTCs) are a prognostic marker in patients with metastatic colorectal cancer (mCRC). However, little is known about the characterization of CTCs in mCRC at the single-cell level using RNA sequencing. The purpose of this study was to validate the capability to detect and isolate single CTCs for single-cell RNA sequencing (scRNA-seq) and to identify clinical significance at a single CTC level. Methods: Single CTCs from 27 mCRC patients were collected by CTC-FIND, which is comprised of filter separation and immunomagnetic depletion to collect ultra-pure CTC samples. To address tumor heterogeneity, CTCs were collected without relying on any traditional CTC markers, such as epithelial and mesenchymal cell antigens, and were undertaken by scRNA-seq using SMART-Seq v4. Results: We identified 59 single CTCs which were classified into four groups by epithelial, epithelial-mesenchymal transition (EMT) and stem cell-related gene expression. Patients receiving second or later-line treatment who had EMT gene expressing CTCs had a significantly shorter PFS and OS. Conclusions: Exploiting CTC-FIND with SMART-Seq v4 showed that scRNA-seq of CTCs may shed new insight into tumor heterogeneity of mCRC and that the presence of CTCs expressing EMT-related genes at the single-cell level could have prognostic value in mCRC patients.

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“…Shin et al reported that exogenous miR-29b mediated an anticancer effect by impeding the activation of ITGA11 [ 36 ]. In our study, by using PPI and GO analyses, ITGA11 was found to have a close association with EMT-related proteins such as TLN1 [ 43 ], FLNA [ 44 ], SPP1 [ 45 ], SPARC [ 46 ] etc., and could be involved in EMT. These results reflected that circRNA_100290 promoted EMT mainly via the miR-29b-3p/ITGA11 axis.…”

Section: Discussionmentioning

confidence: 95%

CircRNA_100290 promotes GC cell proliferation and invasion via the miR-29b-3p/ITGA11 axis and is regulated by EIF4A3

Wang

Sun

2021

Cancer Cell Int

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Background Circular RNAs (circRNAs) have been reported to be important regulators of the development and progression of various carcinomas. However, the role of circRNA_100290 in gastric cancer (GC) is still unclear. This study aimed to investigate the role of circRNA_100290 in GC invasion and metastasis and the possible underlying mechanism. Methods The expression of circRNA_100290 in GC cells and tissues was examined using quantitative real-time polymerase chain reaction (qRT-PCR). The role of circRNA_100290 in cell proliferation, migration, and invasion was evaluated in the AGS and HGC-27 cell lines in vitro. Bioinformatics tools, dual-luciferase reporter assays, Western blot assays and qRT-PCR were used to explore the pathways downstream of circRNA_100290. The mechanism underlying the regulation of circRNA_100290 expression was explored using RNA immunoprecipitation, qRT-PCR, and Western blot assays. Results The expression of circRNA_100290 was significantly upregulated in GC cells and 102 GC tissues, and high circRNA_100290 expression in GC was closely related to Borrmann’s type, lymph node metastasis and tumour-node-metastasis stage. In vitro, knockdown of circRNA_100290 in AGS and HGC-27 cells significantly inhibited cell proliferation, migration, and invasion. Mechanistically, a dual-luciferase reporter assay confirmed the direct interaction between circRNA_100290 and miR-29b-3p, which targets ITGA11, an oncogene that is closely related to epithelial–mesenchymal transition (EMT). In addition, EIF4A3, an RNA-binding protein (RBP), could inhibit the formation of circRNA_100290 by binding to the flanking sites of circRNA_100290. Low EIF4A3 expression in GC was related to a poor prognosis. Conclusions Elevated circRNA_100290 expression in GC promotes cell proliferation, invasion and EMT via the miR-29b-3p/ITGA11 axis and might be regulated by EIF4A3. CircRNA_100290 might be a promising biomarker and target for GC therapy. Graphical abstract

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Role of SPARC in the epithelial-mesenchymal transition induced by PTHrP in human colon cancer cells

Cited by 16 publications

References 55 publications

Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells

Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells

Clinical Significance of Circulating Tumor Cell Induced Epithelial-Mesenchymal Transition in Patients with Metastatic Colorectal Cancer by Single-Cell RNA-Sequencing

CircRNA_100290 promotes GC cell proliferation and invasion via the miR-29b-3p/ITGA11 axis and is regulated by EIF4A3

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