Interleukin-1 receptor antagonist inhibits matastatic potential by down-regulating CXCL12/CXCR4 signaling axis in colorectal cancer

Abstract Background The aim of this study was to investigate the co-operative role of CXCR4/CXCL12 axis and IL-1Ra in metastatic processes mechanism by interactions between colorectal cancer cells and stromal cells in their microenvironment. Methods Expression of IL-1α, interleukin-1 receptor type I (IL-1 RI), CXCL12 and CXCR4 mRNA and proteins were determined by RT-PCR and Western blot. The effect of secreted level of CXCL12 by IL-1Ra on fibroblasts was measured by ELISA. CXCL12 regulate metastatic potential of colorectal cancer was evaluated by proliferation, invasion and angiogenesis assays, respectively, in which invasion and angiogenesis assays used an in vitro system consisting of co-cultured colorectal cells and stromal cells. Results IL-1α was expressed in high liver metastatic colorectal cancer cell lines (HT-29 and WiDr). The colorectal cancer cell-derived IL-1α and rIL-1α significantly promoted CXCL12 expression by fibroblasts, and this enhancing effect can be significantly inhibited by IL-1Ra (P < 0.01). CXCL12 not only enhanced the migration and proliferation of human umbilical vein endothelial cells, but also significantly enhanced angiogenesis (P < 0.01). Furthermore, the high liver-metastatic colorectal cancer cell line (HT-29), which secretes IL-1α, significantly enhanced angiogenesis compared to the low liver-metastatic cell line (CaCo-2), which does not produce IL-1α (P < 0.01). On the contrary, IL-1Ra can significantly inhibit migration, proliferation and angiogenesis (P < 0.01). Conclusion Autocrine IL-1α and paracrine CXCL12 co-enhances the metastatic potential of colorectal cancer cells; IL-1Ra can inhibit the metastatic potential of colorectal cancer cells via decrease IL-1α/CXCR4/CXCL12 signaling pathways. Graphical Abstract

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Interleukin Receptor Antagonist Inhibits Matastatic Potential by Down-Regulating CXCL12/CXCR4 Signaling Axis in Colorectal Cancer

10.21203/rs.3.rs-586339/v1 ◽

2021 ◽

Author(s):

Jiachi Ma ◽

Wanqing Liang ◽

Yaosheng Qiang ◽

Lei Li ◽

Jun Du ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Stromal Cells ◽

Metastatic Potential ◽

Colorectal Cancer Cell ◽

Colorectal Cancer Cells ◽

Ht 29 ◽

High Liver

Abstract Background: The aim of this study was to investigate the co-operative role of CXCR4/ CXCL12 axis and IL-1Ra in metastatic processes mechanism by interactions between colorectal cancer cells and stromal cells in their microenvironment. Methods: Expression of IL-1a, CXCL12 and CXCR4 mRNA and proteins were determined by RT-PCR and Western blot. The effect of secreted level of CXCL12 by IL-1Ra on fibroblasts was measured by ELISA. CXCL12 regulate metastatic potential of colorectal cancer was evaluated by proliferation, invasion and angiogenesis assays, respectively, in which invasion and angiogenesis assays used an in vitro system consisting of co-cultured colorectal cells and stromal cells. Results: IL-1a was expressed in high liver metastatic colorectal cancer cell lines (HT-29 and WiDr). The colorectal cancer cell-derived IL-1a and rIL-1a significantly promoted CXCL12 expression by fibroblasts, and this enhancing effect can be significantly inhibited by IL-1Ra (P<0.01). CXCL12 not only enhanced the migration and proliferation of human umbilical vein endothelial cells (HUVECs), but also significantly enhanced angiogenesis (P<0.01). Furthermore, the high liver-metastatic colorectal cancer cell line (HT-29), which secretes IL-1a, significantly enhanced angiogenesis compared to the low liver-metastatic cell line (CaCo-2), which does not produce IL-1a (P<0.01). On the contrary, IL-1Ra can significantly inhibit migration, proliferation and angiogenesis (P<0.01). Conclusion: Autocrine IL-1a and paracrine CXCL12 co-enhances the metastatic potential of colorectal cancer cells; IL-1Ra can inhibit the metastatic potential of colorectal cancer cells via decrease IL-1a/CXCR4/CXCL12 signaling pathways.

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Interleukin-1 receptor antagonist inhibits matastatic potential by down-regulating CXCL12/CXCR4 signaling axis in colorectal cancer

10.21203/rs.3.rs-742665/v2 ◽

2021 ◽

Author(s):

Jiachi Ma ◽

Wanqing Liang ◽

Yaosheng Qiang ◽

Lei Li ◽

Jun Du ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Stromal Cells ◽

Metastatic Potential ◽

Colorectal Cancer Cell ◽

Colorectal Cancer Cells ◽

Ht 29 ◽

High Liver

Abstract Background The aim of this study was to investigate the co-operative role of CXCR4/ CXCL12 axis and IL-1Ra in metastatic processes mechanism by interactions between colorectal cancer cells and stromal cells in their microenvironment. Methods Expression of IL-1α, CXCL12 and CXCR4 mRNA and proteins were determined by RT-PCR and Western blot. The effect of secreted level of CXCL12 by IL-1Ra on fibroblasts was measured by ELISA. CXCL12 regulate metastatic potential of colorectal cancer was evaluated by proliferation, invasion and angiogenesis assays, respectively, in which invasion and angiogenesis assays used an in vitro system consisting of co-cultured colorectal cells and stromal cells. Results IL-1α was expressed in high liver metastatic colorectal cancer cell lines (HT-29 and WiDr). The colorectal cancer cell-derived IL-1α and rIL-1α significantly promoted CXCL12 expression by fibroblasts, and this enhancing effect can be significantly inhibited by IL-1Ra ( P<0.01 ). CXCL12 not only enhanced the migration and proliferation of human umbilical vein endothelial cells (HUVECs), but also significantly enhanced angiogenesis ( P<0.01 ). Furthermore, the high liver-metastatic colorectal cancer cell line (HT-29), which secretes IL-1α, significantly enhanced angiogenesis compared to the low liver-metastatic cell line (CaCo-2), which does not produce IL-1α ( P<0.01 ). On the contrary, IL-1Ra can significantly inhibit migration, proliferation and angiogenesis ( P<0.01 ). Conclusion Autocrine IL-1α and paracrine CXCL12 co-enhances the metastatic potential of colorectal cancer cells; IL-1Ra can inhibit the metastatic potential of colorectal cancer cells via decrease IL-1α/CXCR4/CXCL12 signaling pathways.

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Interleukin-1 Receptor Antagonist Inhibits Matastatic Potential by Down-Regulating CXCL12/CXCR4 Signaling Axis in Colorectal Cancer

10.21203/rs.3.rs-742665/v1 ◽

2021 ◽

Author(s):

Jiachi Ma ◽

Wanqing Liang ◽

Yaosheng Qiang ◽

Lei Li ◽

Jun Du ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Stromal Cells ◽

Metastatic Potential ◽

Colorectal Cancer Cell ◽

Colorectal Cancer Cells ◽

Ht 29 ◽

High Liver

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PLAC1 Enhances Metastatic Potential and is Associated with PI3K/AKT/NF-κB Signaling Pathway in Colon Cancer

10.21203/rs.2.15971/v1 ◽

2019 ◽

Author(s):

JIachi Ma ◽

Shoukai Zhang ◽

Danru Liang ◽

Lei Li ◽

Jun Du ◽

...

Keyword(s):

Colorectal Cancer ◽

Endothelial Cells ◽

Cancer Cells ◽

Umbilical Vein ◽

Metastatic Potential ◽

Dependent Manner ◽

Human Colorectal Cancer ◽

Colorectal Cancer Cells ◽

Metastatic Process ◽

Ht 29

Abstract Background: To better explore the underlying mechanism of liver metastatic formation by placenta-specific protein 1 (PLAC1) in human colorectal cancer, we investigated the proliferation, invasion and angiogenic capabilities of human colorectal cancer cell lines with different liver metastatic potentials as well as the mechanism of action of PLAC1 in the metastatic process. Methods: The expression of PLAC1 was detected by reverse transcriptase PCR, western blot and real-time PCR. The effect of PLAC1 on metastatic potential was determined by proliferation, invasion, and angiogenesis assays, including an in vitro coculture system consisting of cancer cells and vascular endothelial cells that were used to detect the relationship between cancer cells and angiogenesis. In addition, we also determined PLAC1 downstream targets that preferentially contribute to the metastatic process. Results: PLAC1 was expressed in HT-29, WiDr and CaCo-2 colorectal cancer cells but not in Colo320 colorectal cancer cells. PLAC1 could not only significantly enhance the proliferation of CoLo320 and human umbilical vein endothelial cells (HUVECs) but could also promote the invasion of CoLo320 cells. The angiogenesis of HUVECs was enhanced by PLAC1 in a dose-dependent manner. In cocultured systems, angiogenesis was significantly increased by coculture with HT-29 cells. In addition, PLAC1 could promote angiogenesis in coculture with HT-29 cells. Furthermore, PLAC1-enhanced metastatic potential of colorectal cancer cells was dependent on activation of the PI3K/Akt/NF-κB pathway. Conclusions: The activation of PI3K/Akt/NF-κB signaling by PLAC1 may be critical for the metastasis of colorectal cancer cells. According to our results, we suggest that modification of PLAC1 function might be a promising new therapeutic approach to inhibit the aggressive spread of colorectal cancer.

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An Integrated Bioinformatics Analysis Repurposes an Antihelminthic Drug Niclosamide for Treating HMGA2-Overexpressing Human Colorectal Cancer

Cancers ◽

10.3390/cancers11101482 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1482 ◽

Cited By ~ 6

Author(s):

Leung ◽

Chou ◽

Huang ◽

Yang

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Gene Signature ◽

Cancer Cell Lines ◽

Colorectal Cancer Cell ◽

Sequencing Analysis ◽

Colorectal Cancer Cells ◽

Colorectal Cancer Cell Lines

Aberrant overexpression of high mobility group AT-hook 2 (HMGA2) is frequently found in cancers and HMGA2 has been considered an anticancer therapeutic target. In this study, a pan-cancer genomics survey based on Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) data indicated that HMGA2 was mainly overexpressed in gastrointestinal cancers including colorectal cancer. Intriguingly, HMGA2 overexpression had no prognostic impacts on cancer patients’ overall and disease-free survivals. In addition, HMGA2-overexpressing colorectal cancer cell lines did not display higher susceptibility to a previously identified HMGA2 inhibitor (netroposin). By microarray profiling of HMGA2-driven gene signature and subsequent Connectivity Map (CMap) database mining, we identified that S100 calcium-binding protein A4 (S100A4) may be a druggable vulnerability for HMGA2-overexpressing colorectal cancer. A repurposing S100A4 inhibitor, niclosamide, was found to reverse the HMGA2-driven gene signature both in colorectal cancer cell lines and patients’ tissues. In vitro and in vivo experiments validated that HMGA2-overexpressing colorectal cancer cells were more sensitive to niclosamide. However, inhibition of S100A4 by siRNAs and other inhibitors was not sufficient to exert effects like niclosamide. Further RNA sequencing analysis identified that niclosamide inhibited more cell-cycle-related gene expression in HMGA2-overexpressing colorectal cancer cells, which may explain its selective anticancer effect. Together, our study repurposes an anthelminthic drug niclosamide for treating HMGA2-overexpression colorectal cancer.

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A Low-Cost and Portable Smart Instrumentation for Detecting Colorectal Cancer Cells

Applied Sciences ◽

10.3390/app9173510 ◽

2019 ◽

Vol 9 (17) ◽

pp. 3510 ◽

Cited By ~ 1

Author(s):

Mohammad Wajih Alam ◽

Khan A. Wahid ◽

Md. Fahmid Islam ◽

Wendy Bernhard ◽

Clarence R. Geyer ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Mammalian Cells ◽

Imaging System ◽

Low Cost ◽

Colorectal Cancer Cell ◽

Colorectal Cancer Cell Line ◽

Visible Range ◽

Colorectal Cancer Cells

Fluorescence imaging is a well-known method for monitoring fluorescence emitted from the subject of interest and provides important insights about cell dynamics and molecules in mammalian cells. Currently, many solutions exist for measuring fluorescence, but the application methods are complex and the costs are high. This paper describes the design and development of a low-cost, smart and portable fluorimeter for the detection of colorectal cancer cell expressing IRFP702. A flashlight is used as a light source, which emits light in the visible range and acts as an excitation source, while a photodiode is used as a detector. It also uses a longpass filter to only allow the wavelength of interest to pass from the cultured cell. It eliminates the need of both the dichroic mirror and excitation filter, which makes the developed device low cost, compact and portable as well as lightweight. The custom-built sample chamber is black in color to minimize interference and is printed with a 3D printer to accommodate the detector circuitry. An established colorectal cancer cell line (human colorectal carcinoma (HCT116)) was cultured in the laboratory environment. A near-infrared fluorescent protein IRFP702 was expressed in the colorectal cancer cells that were used to test the proof-of-concept. The fluorescent cancer cells were first tested with a commercial imaging system (Odyssey® CLx) and then with the developed prototype to validate the result in a preclinical setting. The developed fluorimeter is versatile as it can also be used to detect multiple types of cancer cells by simply replacing the filters based on the fluorophore.

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Placenta-Specific Protein 1 Enhances Liver Metastatic Potential and is Associated with the PI3K/AKT/NF-κB Signaling Pathway in Colorectal Cancer

10.21203/rs.2.24480/v2 ◽

2020 ◽

Author(s):

Jiachi Ma ◽

Lei Li ◽

Jun Du ◽

Chengwu Pan ◽

Chensong Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Endothelial Cells ◽

Cancer Cells ◽

Metastatic Potential ◽

Specific Protein ◽

Dependent Manner ◽

Human Colorectal Cancer ◽

Colorectal Cancer Cells ◽

Metastatic Process ◽

Ht 29

Abstract Abstract Background: To better explore the underlying mechanism of liver metastatic formation by placenta-specific protein 1 (PLAC1) in human colorectal cancer, we investigated the proliferation, invasion and angiogenic capabilities of human colorectal cancer cell lines with different liver metastatic potentials as well as the mechanism of action of PLAC1 in the metastatic process. Methods: The expression of PLAC1 was detected by reverse transcriptase PCR, western blot and real-time PCR. The effect of PLAC1 on metastatic potential was determined by proliferation, invasion, and angiogenesis assays, including an in vitro coculture system consisting of cancer cells and vascular endothelial cells that were used to detect the relationship between cancer cells and angiogenesis. In addition, we also determined PLAC1 downstream targets that preferentially contribute to the metastatic process. Results: PLAC1 was expressed in HT-29, WiDr and CaCo-2 colorectal cancer cells but not in Colo320 colorectal cancer cells. PLAC1 not only enhanced significantly the proliferation of CoLo320 and human umbilical vein endothelial cells (HUVECs), but also promoted the invasion of CoLo320 cells. The angiogenesis of HUVECs was enhanced by PLAC1 in a dose-dependent manner. In cocultured systems, angiogenesis was significantly increased by coculture with HT-29 cells. In addition, PLAC1 could promote angiogenesis in coculture with HT-29 cells. Furthermore, PLAC1-enhanced metastatic potential of colorectal cancer cells was dependent on activation of the PI3K/Akt/NF-κB pathway. Conclusions: The activation of PI3K/Akt/NF-κB signaling by PLAC1 may be critical for the metastasis of colorectal cancer cells. According to our results, we suggest that modification of PLAC1 function might be a promising new therapeutic approach to inhibit the aggressive spread of colorectal cancer.

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Surface-bound galectin-4 regulates gene transcription and secretion of chemokines in human colorectal cancer cell lines

Tumor Biology ◽

10.1177/1010428317691687 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769168 ◽

Cited By ~ 5

Author(s):

U Subrahmanyeswara Rao ◽

Prema S Rao

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Cell Surface ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Colorectal Cancer Cell ◽

Colorectal Tumorigenesis ◽

Colorectal Cancer Cells ◽

Colorectal Cancer Cell Lines

One long-term complication of chronic intestinal inflammation is the development of colorectal cancer. However, the mechanisms linking inflammation to the colorectal tumorigenesis are poorly defined. Previously, we have demonstrated that galectin-4 is predominantly expressed in the luminal epithelia of the gastrointestinal tract, and its loss of expression plays a key role in the colorectal tumorigenesis. However, the mechanism by which galectin-4 regulates inflammation-induced tumorigenesis is unclear. Here, we show that galectin-4 secreted by the colorectal cancer cell lines was bound to the cell surface. Neutralization of surface-bound galectin-4 with anti-galectin-4 antibody resulted in increased cell proliferation with concomitant secretion of several chemokines into the extracellular medium. Neutralization of the surface-bound galectin-4 also resulted in the up-regulation of transcription of 29 genes, several of which are components of multiple inflammation signaling pathways. In an alternate experiment, binding of recombinant galectin-4 protein to cell surface of the galectin-4-negative colorectal cancer cells resulted in increased p27, and decreased cyclin D1 and c-Myc levels, leading to cell cycle arrest and apoptosis. Together, these data demonstrated that surface-bound galectin-4 is a dual function protein—down-regulating cell proliferation and chemokine secretion in galectin-4-expressing colorectal cancer cells on one hand and inducing apoptosis in galectin-4-negative colorectal cancer cells on the other hand.

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Sponges from North Borneo and their bioactivity against human colorectal cancer cells

Borneo Journal of Marine Science and Aquaculture (BJoMSA) ◽

10.51200/bjomsa.v2i0.1215 ◽

2018 ◽

Vol 2 ◽

pp. 40-47

Author(s):

Yoong Soon Yong ◽

Swee-Cheng Lim ◽

Ping-Chin Lee ◽

Yee-Soon Ling

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Marine Sponges ◽

Colorectal Cancer Cell ◽

Human Colorectal Cancer ◽

Cytotoxicity Activity ◽

North Borneo ◽

Wide Range ◽

Colorectal Cancer Cells

Invertebrates are a major reservoir for numerous cytotoxic compounds that are used to defence themselves against prey and adaptation towards the environment. Throughout the years, numerous studies discovered from sponge extracts were effective against a wide range of cancer cells. In this study, 23 sponges comprising of some 19 species were collected from Northeast Borneo. Sponges were treated and extracted using modified Folch extraction method, followed by cytotoxicity assay to determine their effectiveness against different colorectal cancer cells. From the results, Monanchora clathrate, Dysidea sp., and Jaspis sp. were found to possess different degrees of cytotoxicity against wide range of human colorectal cancer cell. Monanchora clathrate (KDT07), Dysidea sp. (KDT09), and Jaspis sp. (KDT18) are among the demosponges which possess significant cytotoxicity against colorectal cancer cell lines, including HCT116, LoVo, SW480, and SW620. Besides, we found that environmental factors tend to alter chemical yield from the different species under the same genera. Among them, KDT08 and KDT21 which fall under same genus Dysidea, yet possess insignificant cytotoxicity against colorectal cancer cells. This research article provides a preliminary test for cytotoxicity activity of a wide range of marine sponges. Throughout this study, acquired results could provide useful information to determine the worthiness to further isolate nor purify the nature product from these sponges.

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