|
1
|
Borodulina OR, Kosushkin SA, Ustyantsev IG, Vassetzky NS, Kramerov DA. Analysis of RNA Transcribed by RNA Polymerase III from B2 SINEs in Mouse Cells. Noncoding RNA 2025; 11:39. [PMID: 40407597 PMCID: PMC12101331 DOI: 10.3390/ncrna11030039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2025] [Revised: 05/02/2025] [Accepted: 05/12/2025] [Indexed: 05/26/2025] Open
Abstract
Background/Objectives: SINEs (short interspersed elements) are eukaryotic non-autonomous retrotransposons. They are transcribed by RNA polymerase III (pol III) and generate non-coding RNAs. The 3' end of many mammalian SINEs contains a polyadenylation signal (AATAAA), a pol III transcription terminator, and an A-rich tail. Studies have shown that, in human HeLa cells that have been transiently transfected with such SINEs, short pol III-generated SINE transcripts undergo polyadenylation, resulting in the addition of a long poly(A)-tail. Notably, this AAUAAA-dependent polyadenylation is not characteristic of any other transcripts synthesized by pol III. B2 SINEs, found in the genomes of mouse-like rodents, exemplify all these features. Methods: In this study, we implemented a novel approach to sequencing pol III-generated B2 transcripts from mouse cell cultures (L929 and 4T1) and organs (brain and testis). Results: Transcription occurred in 16,000-20,000 B2 copies in each cell type, 51-62% of which were transcribed in all four cell types. Effective transcription terminators (e.g., TCT>3 and T≥4) were found in approximately 40% of the transcribed B2 copies. The transcripts of these B2 copies contained a truncated terminator sequence, as pol III transcriptional arrest is known to occur within the terminator, with a poly(A)-tail immediately downstream. Such a tail could only have formed through RNA polyadenylation. Conclusions: These results demonstrate that B2 transcripts synthesized by pol III are capable of polyadenylation in mouse cells. We discuss the transcription of B2 copies with and without moderately efficient pol III terminators (TCTTT) and provide examples of the polyadenylation of such transcripts.
Collapse
Affiliation(s)
- Olga R. Borodulina
- Laboratory of Eukaryotic Genome Evolution, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.R.B.); (I.G.U.); (N.S.V.)
| | | | - Ilia G. Ustyantsev
- Laboratory of Eukaryotic Genome Evolution, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.R.B.); (I.G.U.); (N.S.V.)
| | - Nikita S. Vassetzky
- Laboratory of Eukaryotic Genome Evolution, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.R.B.); (I.G.U.); (N.S.V.)
| | - Dmitri A. Kramerov
- Laboratory of Eukaryotic Genome Evolution, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (O.R.B.); (I.G.U.); (N.S.V.)
| |
Collapse
|
|
2
|
Harada Y, Ikeda S, Kawabe Y, Oguri Y, Hashimura M, Yokoi A, Sida A, Fukagawa N, Hayashi M, Ono M, Kusano C, Takahashi H, Saegusa M. S100A4 contributes to colorectal carcinoma aggressive behavior and to chemoradiotherapy resistance in locally advanced rectal carcinoma. Sci Rep 2024; 14:31338. [PMID: 39732925 PMCID: PMC11682060 DOI: 10.1038/s41598-024-82814-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 12/09/2024] [Indexed: 12/30/2024] Open
Abstract
To investigate the functional role of S100A4 in advanced colorectal carcinoma (Ad-CRC) and locally advanced rectal carcinoma (LAd-RC) receiving neoadjuvant chemoradiotherapy (NCRT). We analyzed histopathological and immunohistochemical sections from 150 patients with Ad-CRC and 177 LAd-RC patients treated with NCRT. S100A4 knockout (KO) HCT116 cells were also used. S100A4 expression was absent in normal mucosa but increased progressively from colorectal adenoma to carcinoma, suggesting that S100A4 regulation is an early event in colorectal carcinogenesis. In Ad-CRC, high S100A4 expression correlated with high tumor budding and nuclear β-catenin, deep invasion, lymph-vascular involvement, and unfavorable prognosis. In NCRT-treated LAd-RC, high S100A4 expression was associated with poor treatment response and short progression-free survival. S100A4 KO decreased the proliferation of HCT116 cells through activation of the p53/p21waf1 axis, and sensitized cells to adriamycin-induced apoptosis. Levels of the apoptotic marker, cleaved poly (ADP-ribose) polymerase 1, were significantly higher in samples with low S100A4 and wild type p53. Finally, we observed a direct interaction between S100A4 and p53. In conclusion, S100A4 expression engenders aggressive behavior in Ad-CRC through association with β-catenin-driven tumor buddings. S100A4 exerts anti-apoptotic and proliferative effects via inhibition of p53 in LAd-RC patients receiving NCRT, which leads to chemoradioresistance and poor prognosis.
Collapse
Affiliation(s)
- Yohei Harada
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
- Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Sayako Ikeda
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Yuna Kawabe
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Yasuko Oguri
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Miki Hashimura
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Ako Yokoi
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Akiko Sida
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Naomi Fukagawa
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
- Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Misato Hayashi
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Mototsugu Ono
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
- Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
- Department of Pathology, Kitasato University School of Allied Health Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Chika Kusano
- Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Hiroyuki Takahashi
- Department of Pathology, Kitasato University School of Allied Health Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Makoto Saegusa
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan.
| |
Collapse
|
|
3
|
Li A, Zhu L, Lei N, Wan J, Duan X, Liu S, Cheng Y, Wang M, Gu Z, Zhang H, Bai Y, Zhang L, Wang F, Ni C, Qin Z. S100A4-dependent glycolysis promotes lymphatic vessel sprouting in tumor. Angiogenesis 2023; 26:19-36. [PMID: 35829860 DOI: 10.1007/s10456-022-09845-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 06/20/2022] [Indexed: 01/12/2023]
Abstract
Tumor-induced lymphangiogenesis promotes the formation of new lymphatic vessels, contributing to lymph nodes (LNs) metastasis of tumor cells in both mice and humans. Vessel sprouting appears to be a critical step in this process. However, how lymphatic vessels sprout during tumor lymphangiogenesis is not well-established. Here, we report that S100A4 expressed in lymphatic endothelial cells (LECs) promotes lymphatic vessel sprouting in a growing tumor by regulating glycolysis. In mice, the loss of S100A4 in a whole body (S100A4-/-), or specifically in LECs (S100A4ΔLYVE1) leads to impaired tumor lymphangiogenesis and disrupted metastasis of tumor cells to sentinel LNs. Using a 3D spheroid sprouting assay, we found that S100A4 in LECs was required for the lymphatic vessel sprouting. Further investigations revealed that S100A4 was essential for the position and motility of tip cells, where it activated AMPK-dependent glycolysis during lymphatic sprouting. In addition, the expression of S100A4 in LECs was upregulated under hypoxic conditions. These results suggest that S100A4 is a novel regulator of tumor-induced lymphangiogenesis. Targeting S100A4 in LECs may be a potential therapeutic strategy for lymphatic tumor metastasis.
Collapse
Affiliation(s)
- Anqi Li
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, The Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
| | - Linyu Zhu
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
| | - Ningjing Lei
- School of Basic Medical Sciences, The Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
| | - Jiajia Wan
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Xixi Duan
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Shuangqing Liu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yanru Cheng
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Ming Wang
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhuoyu Gu
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Huilei Zhang
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yueyue Bai
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Li Zhang
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Fazhan Wang
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Chen Ni
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhihai Qin
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
4
|
RAGE Inhibitors for Targeted Therapy of Cancer: A Comprehensive Review. Int J Mol Sci 2022; 24:ijms24010266. [PMID: 36613714 PMCID: PMC9820344 DOI: 10.3390/ijms24010266] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/28/2022] [Accepted: 12/16/2022] [Indexed: 12/28/2022] Open
Abstract
The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin family that is overexpressed in several cancers. RAGE is highly expressed in the lung, and its expression increases proportionally at the site of inflammation. This receptor can bind a variety of ligands, including advanced glycation end products, high mobility group box 1, S100 proteins, adhesion molecules, complement components, advanced lipoxidation end products, lipopolysaccharides, and other molecules that mediate cellular responses related to acute and chronic inflammation. RAGE serves as an important node for the initiation and stimulation of cell stress and growth signaling mechanisms that promote carcinogenesis, tumor propagation, and metastatic potential. In this review, we discuss different aspects of RAGE and its prominent ligands implicated in cancer pathogenesis and describe current findings that provide insights into the significant role played by RAGE in cancer. Cancer development can be hindered by inhibiting the interaction of RAGE with its ligands, and this could provide an effective strategy for cancer treatment.
Collapse
|
|
5
|
Dihydromyricetin Inhibited Migration and Invasion by Reducing S100A4 Expression through ERK1/2/β-Catenin Pathway in Human Cervical Cancer Cell Lines. Int J Mol Sci 2022; 23:ijms232315106. [PMID: 36499426 PMCID: PMC9735508 DOI: 10.3390/ijms232315106] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/25/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022] Open
Abstract
Cervical cancer has a poor prognosis and is the fourth most common cancer among women. Dihydromyricetin (DHM), a flavonoid compound, exhibits several pharmacological activities, including anticancer effects; however, the effects of DHM on cervical cancer have received insufficient research attention. This study examined the antitumor activity and underlying mechanisms of DHM on human cervical cancer. Our results indicated that DHM inhibits migration and invasion in HeLa and SiHa cell lines. Mechanistically, RNA sequencing analysis revealed that DHM suppressed S100A4 mRNA expression in HeLa cells. Moreover, DHM inhibited the protein expressions of β-catenin and GSK3β through the regulated extracellular-signal-regulated kinase (ERK)1/2 signaling pathway. By using the ERK1/2 activator, T-BHQ, reverted β-catenin and S100A4 protein expression and cell migration, which were reduced in response to DHM. In conclusion, our study indicated that DHM inhibited cell migration by reducing the S100A4 expression through the ERK1/2/β-catenin pathway in human cervical cancer cell lines.
Collapse
|
|
6
|
Santolla MF, Talia M, Maggiolini M. S100A4 Is Involved in Stimulatory Effects Elicited by the FGF2/FGFR1 Signaling Pathway in Triple-Negative Breast Cancer (TNBC) Cells. Int J Mol Sci 2021; 22:ijms22094720. [PMID: 33946884 PMCID: PMC8124532 DOI: 10.3390/ijms22094720] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/23/2021] [Accepted: 04/27/2021] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype characterized by poor clinical outcome. In recent years, numerous advancements have been made to better understand the biological landscape of TNBC, though appropriate targets still remain to be determined. In the present study, we have determined that the expression levels of FGF2 and S100A4 are higher in TNBC with respect to non-TNBC patients when analyzing “The Invasive Breast Cancer Cohort of The Cancer Genome Atlas” (TCGA) dataset. In addition, we have found that the gene expression of FGF2 is positively correlated with S100A4 in TNBC samples. Performing quantitative PCR, Western blot, CRISPR/Cas9 genome editing, promoter studies, immunofluorescence analysis, subcellular fractionation studies, and ChIP assays, we have also demonstrated that FGF2 induces in TNBC cells the upregulation and secretion of S100A4 via FGFR1, along with the ERK1/2–AKT–c-Rel transduction signaling. Using conditioned medium from TNBC cells stimulated with FGF2, we have also ascertained that the paracrine activation of the S100A4/RAGE pathway triggers angiogenic effects in vascular endothelial cells (HUVECs) and promotes the migration of cancer-associated fibroblasts (CAFs). Collectively, our data provide novel insights into the action of the FGF2/FGFR1 axis through S100A4 toward stimulatory effects elicited in TNBC cells.
Collapse
MESH Headings
- Antigens, Neoplasm/physiology
- Cell Movement/drug effects
- Culture Media, Conditioned/pharmacology
- Female
- Fibroblast Growth Factor 2/pharmacology
- Fibroblast Growth Factor 2/physiology
- Fibroblasts/pathology
- Gene Expression Regulation, Neoplastic/physiology
- Human Umbilical Vein Endothelial Cells
- Humans
- Mitogen-Activated Protein Kinases/physiology
- Neoplasm Proteins/physiology
- Neovascularization, Pathologic/physiopathology
- Paracrine Communication
- Protein Kinase Inhibitors/pharmacology
- Proto-Oncogene Proteins c-rel/physiology
- Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- Receptor, Fibroblast Growth Factor, Type 1/physiology
- S100 Calcium-Binding Protein A4/physiology
- Signal Transduction/drug effects
- Signal Transduction/physiology
- Triple Negative Breast Neoplasms/blood supply
- Triple Negative Breast Neoplasms/physiopathology
- Tumor Cells, Cultured
Collapse
|
|
7
|
Chengling L, Yulin Z, Xiaoyu X, Xingchen L, Sen Z, Ziming W, Xianming C. miR-325-3p, a novel regulator of osteoclastogenesis in osteolysis of colorectal cancer through targeting S100A4. Mol Med 2021; 27:23. [PMID: 33691630 PMCID: PMC7944890 DOI: 10.1186/s10020-021-00282-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 02/15/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND To investigate effect of microRNA-325-3p (miR-325-3p) on bone metastasis of colorectal cancer (CRC) and the precise role on osteoclastogenesis. METHODS CT-26 cells were injected into tibias to establish bone metastatic model of CRC in vivo. AgomiR-325-3p or antagomir-325-3p were injected in tail-veins of Balb/c mice to interfere the osteoclastogenesis and bone metastasis of CRC. Safranin O and Fast Green staining examined the changes of trabecular area and TRAP staining examined the osteoclast number in bone metastasis of CRC. Real-time PCR was conducted to test the RNA level of miR-325-3p and mRNA levels of TRAP and Cathepsin K in osteoclast precursors (OCPs). Dual-luciferase reporter system was utilized to identify the direct target of miR-325-3p. Conditioned medium from CT-26 cells was collected to stimulate the OCPs during osteoclastogenesis induced by RANKL and M-CSF in vitro. Western blot analysis was performed to examine the protein level of S100A4 in OCPs after interfered by agomiR-325-3p or antagomir-325-3p cultured in CM or not. RESULTS miR-325-3p downregulated in OCPs in CRC microenvironment both in vivo and in vitro. By luciferase activity assay, S100A4 was the target gene of miR-325-3p and the protein level of S100A4 in OCPs upregulated in CRC microenvironment. Overexpression of miR-325-3p inhibited the osteoclastogenesis of OCPs and it can be reversed after transfection with plasmid containing S100A4. Treatment with miR-325-3p can preserve trabecular area in bone metastasis of CRC. CONCLUSION miR-325-3p can prevent osteoclast formation through targeting S100A4 in OCPs. Overexpression of miR-325-3p efficiently decreased the osteoclast number and attenuated bone resorption in bone metastasis of CRC.
Collapse
Affiliation(s)
- Li Chengling
- Daping Hospital of Army Medical University, Chongqing, 400042 People’s Republic of China
| | - Zhang Yulin
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, 400030 People’s Republic of China
| | - Xie Xiaoyu
- Daping Hospital of Army Medical University, Chongqing, 400042 People’s Republic of China
| | - Lu Xingchen
- Daping Hospital of Army Medical University, Chongqing, 400042 People’s Republic of China
| | - Zhang Sen
- Daping Hospital of Army Medical University, Chongqing, 400042 People’s Republic of China
| | - Wang Ziming
- Daping Hospital of Army Medical University, Chongqing, 400042 People’s Republic of China
| | - Chen Xianming
- Daping Hospital of Army Medical University, Chongqing, 400042 People’s Republic of China
| |
Collapse
|
|
8
|
Maddala R, Gao J, Mathias RT, Lewis TR, Arshavsky VY, Levine A, Backer JM, Bresnick AR, Rao PV. Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract. Sci Rep 2021; 11:2203. [PMID: 33500475 PMCID: PMC7838418 DOI: 10.1038/s41598-021-81611-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/05/2021] [Indexed: 11/21/2022] Open
Abstract
S100A4, a member of the S100 family of multifunctional calcium-binding proteins, participates in several physiological and pathological processes. In this study, we demonstrate that S100A4 expression is robustly induced in differentiating fiber cells of the ocular lens and that S100A4 (-/-) knockout mice develop late-onset cortical cataracts. Transcriptome profiling of lenses from S100A4 (-/-) mice revealed a robust increase in the expression of multiple photoreceptor- and Müller glia-specific genes, as well as the olfactory sensory neuron-specific gene, S100A5. This aberrant transcriptional profile is characterized by corresponding increases in the levels of proteins encoded by the aberrantly upregulated genes. Ingenuity pathway network and curated pathway analyses of differentially expressed genes in S100A4 (-/-) lenses identified Crx and Nrl transcription factors as the most significant upstream regulators, and revealed that many of the upregulated genes possess promoters containing a high-density of CpG islands bearing trimethylation marks at histone H3K27 and/or H3K4, respectively. In support of this finding, we further documented that S100A4 (-/-) knockout lenses have altered levels of trimethylated H3K27 and H3K4. Taken together, our findings suggest that S100A4 suppresses the expression of retinal genes during lens differentiation plausibly via a mechanism involving changes in histone methylation.
Collapse
Affiliation(s)
- Rupalatha Maddala
- Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA.
| | - Junyuan Gao
- Department of Physiology and Biophysics, Stony Brook University, Stony-Brook, NY, USA
| | - Richard T Mathias
- Department of Physiology and Biophysics, Stony Brook University, Stony-Brook, NY, USA
| | - Tylor R Lewis
- Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA
| | - Vadim Y Arshavsky
- Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Adriana Levine
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Jonathan M Backer
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Anne R Bresnick
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ponugoti V Rao
- Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA.
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
| |
Collapse
|
|
9
|
Yashin DV, Sashchenko LP, Georgiev GP. Mechanisms of Action of the PGLYRP1/Tag7 Protein in Innate and Acquired Immunity. Acta Naturae 2021; 13:91-101. [PMID: 33959389 PMCID: PMC8084298 DOI: 10.32607/actanaturae.11102] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/19/2020] [Indexed: 11/20/2022] Open
Abstract
One of the promising fields of modern molecular biology is the search for new proteins that regulate the various stages of the immune response and the investigation of the molecular mechanisms of action of these proteins. Such proteins include the multifunctional protein PGLYRP1/Tag7, belonging to the PGRP-S protein family, whose gene was discovered in mice at the Institute of Gene Biology, Russian Academy of Sciences, in 1996. PGLYRP1/Tag7 is classified as a protein of innate immunity; however, it can also participate in the regulation of acquired immunity mechanisms. In this paper, we consider the involvement of PGLYRP1/Tag7 in the triggering of antimicrobial defense mechanisms and formation of subsets of cytotoxic lymphocytes that kill tumor cells. The paper emphasizes that the multifaceted functional activity of Tag7 in the immune response has to do with its ability to interact with various proteins to form stable protein complexes. Hsp70-associated Tag7 can induce the death of tumor cells carrying the TNFR1 receptor. Tag7, associated with the Mts1 (S100A4) protein, can stimulate the migration of innate and adaptive immune cytotoxic lymphocytes to a lesion site. Involvement of Tag7 in the regulation of immunological processes suggests that it may be considered as a promising agent in cancer therapy. These properties of Tag7 were used to develop autologous vaccines that have passed the first and second phases of clinical trials in patients with end-stage melanoma and renal cancer. The C-terminal peptide of Tag7, isolated by limited proteolysis, was shown to protect the cartilage and bone tissue of the ankle joint in mice with induced autoimmune arthritis and may be a promising drug for suppressing the development of inflammatory processes.
Collapse
Affiliation(s)
- D. V. Yashin
- Institute of Gene Biology RAS, Moscow, 119334 Russia
| | | | | |
Collapse
|
|
10
|
Wu Y, Zhang W, Gunst SJ. S100A4 is secreted by airway smooth muscle tissues and activates inflammatory signaling pathways via receptors for advanced glycation end products. Am J Physiol Lung Cell Mol Physiol 2020; 319:L185-L195. [PMID: 32432920 DOI: 10.1152/ajplung.00347.2019] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
S100A4 is a low-molecular-mass (12 kDa) EF-hand Ca2+-binding S100 protein that is expressed in a broad range of normal tissue and cell types. S100A4 can be secreted from some cells to act in an autocrine or paracrine fashion on target cells and tissues. S100A4 has been reported in the extracellular fluids of subjects with several inflammatory diseases, including asthma. Airway smooth muscle plays a critical role in airway inflammation by synthesizing and secreting inflammatory cytokines. We hypothesized that S100A4 may play an immunomodulatory role in airway smooth muscle. Trachealis smooth muscle tissues were stimulated with recombinant His-S100A4, and the effects on inflammatory responses were evaluated. S100A4 induced the activation of Akt and NF-κB and stimulated eotaxin secretion. It also increased the expression of RAGE and endogenous S100A4 in airway tissues. Stimulation of airway smooth muscle tissues with IL-13 or TNF-α induced the secretion of S100A4 from the tissues and promoted the expression of endogenous receptors for advanced glycation end products (RAGE) and S100A4. The role of RAGE in mediating the responses to S100A4A was evaluated by expressing a mutant nonfunctional RAGE (RAGEΔcyto) in tracheal muscle tissues and by treating tissues with a RAGE inhibitor. S100A4 did not activate NF-κB or Akt in tissues that were expressing RAGEΔcyto or treated with a RAGE inhibitor, indicating that S100A4 mediates its effects by acting on RAGE. Our results demonstrate that inflammatory mediators stimulate the synthesis and secretion of S100A4 in airway smooth muscle tissues and that extracellular S100A4 acts via RAGE to mediate airway smooth muscle inflammation.
Collapse
Affiliation(s)
- Yidi Wu
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Wenwu Zhang
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Susan J Gunst
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana
| |
Collapse
|
|
11
|
Fei F, Liu K, Li C, Du J, Wei Z, Li B, Li Y, Zhang Y, Zhang S. Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer. Front Oncol 2020; 10:182. [PMID: 32154176 PMCID: PMC7047322 DOI: 10.3389/fonc.2020.00182] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 02/03/2020] [Indexed: 01/09/2023] Open
Abstract
Recently, an increasing number of evidences have shown that polyploid giant cancer cells (PGCCs) could generate daughter cells with a strong migration and invasion ability, which have been implicated in cancer recurrence and metastasis. However, the underlying molecular mechanisms of PGCCs with their daughter cells remain largely unclear. In vitro and in vivo experiments combined with 222 cases of human colorectal cancer (CRC) samples were used to identify the molecular mechanisms of S100A4-related proteins regulating the invasion and metastasis of PGCCs with their daughter cells. PGCCs with their daughter cells had high migration, invasion, and proliferation abilities compared to control cells; these were significantly inhibited after S100A4 knockdown. The high expression of cathepsin B, cyclin B1, TRIM21, and Annexin A2 were significantly downregulated after S100A4 knockdown, while the overexpression of S100A4, cathepsin B, cyclin B1, and S100A10 were significantly downregulated after TRIM21 knockdown in PGCCs with their daughter cells. The tumorigenic and metastatic ability of PGCCs with their daughter cells in vivo was significantly stronger compared to the untreated cells, which was significantly decreased after S100A4 knockdown. Moreover, the expression of S100A4-related proteins was positively correlated with the malignancy degree of human CRC, and maintained a high level in lymph node metastasis. S100A4 and TRIM21 may regulate each other to affect the expression and subcellular localization of cyclin B1, and participate in regulating the structure and function of Annexin A2/S100A10 complex, affecting downstream cathepsin B, resulting in the invasion and metastasis of PGCCs with their daughter cells. Besides, 14-3-3 ζ/δ and Ezrin may be involved in the motility and invasion of PGCCs with their daughter cells via cytoskeletal constructions with S100A4.
Collapse
Affiliation(s)
- Fei Fei
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Kai Liu
- Graduate School, Tianjin Medical University, Tianjin, China
| | - Chunyuan Li
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Jiaxing Du
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhen Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Bo Li
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuwei Li
- Departments of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Yi Zhang
- Departments of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| |
Collapse
|
|
12
|
Role of S100 proteins in health and disease. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118677. [PMID: 32057918 DOI: 10.1016/j.bbamcr.2020.118677] [Citation(s) in RCA: 195] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 01/22/2020] [Accepted: 02/09/2020] [Indexed: 12/16/2022]
Abstract
The S100 family of proteins contains 25 known members that share a high degree of sequence and structural similarity. However, only a limited number of family members have been characterized in depth, and the roles of other members are likely undervalued. Their importance should not be underestimated however, as S100 family members function to regulate a diverse array of cellular processes including proliferation, differentiation, inflammation, migration and/or invasion, apoptosis, Ca2+ homeostasis, and energy metabolism. Here we detail S100 target protein interactions that underpin the mechanistic basis to their function, and discuss potential intervention strategies targeting S100 proteins in both preclinical and clinical situations.
Collapse
|
|
13
|
Taxerås SD, Galán M, Campderros L, Piquer‐Garcia I, Pellitero S, Martínez E, Puig R, Lucena I, Tarascó J, Moreno P, Balibrea J, Bel J, Murillo M, Martínez M, Ramon‐Krauel M, Puig‐Domingo M, Villarroya F, Lerin C, Sánchez‐Infantes D. Differential association between S100A4 levels and insulin resistance in prepubertal children and adult subjects with clinically severe obesity. Obes Sci Pract 2020; 6:99-106. [PMID: 32128247 PMCID: PMC7042100 DOI: 10.1002/osp4.381] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/09/2019] [Accepted: 10/07/2019] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES S100A4 has been recently identified as an adipokine associated with insulin resistance (IR) in adult subjects with obesity. However, no data about its levels in children with obesity and only a few approaches regarding its potential mechanism of action have been reported. To obtain a deeper understanding of the role of S100A4 in obesity, (a) S100A4 levels were measured in prepubertal children and adult subjects with and without obesity and studied the relationship with IR and (b) the effects of S100A4 in cultured human adipocytes and vascular smooth muscle cells (VSMCs) were determined. METHODS Sixty-five children (50 with obesity, age 9.0 ±1.1 years and 15 normal weight, age 8.4 ±0.8 years) and fifty-nine adults (43 with severe obesity, age 46 ±11 years and 16 normal weight, age 45 ±9 years) were included. Blood from children and adults and adipose tissue samples from adults were obtained and analysed. Human adipocytes and VSMC were incubated with S100A4 to evaluate their response to this adipokine. RESULTS Circulating S100A4 levels were increased in both children (P = .002) and adults (P < .001) with obesity compared with their normal-weight controls. In subjects with obesity, S100A4 levels were associated with homeostatic model assessment-insulin resistance (HOMA-IR) in adults (βstd = .42, P = .008) but not in children (βstd = .12, P = .356). Human adipocytes were not sensitive to S100A4, while incubation with this adipokine significantly reduced inflammatory markers in VSMC. CONCLUSIONS Our human data demonstrate that higher S100A4 levels are a marker of IR in adults with obesity but not in prepubertal children. Furthermore, the in vitro results suggest that S100A4 might exert an anti-inflammatory effect. Further studies will be necessary to determine whether S100A4 can be a therapeutic target for obesity.
Collapse
Affiliation(s)
- Siri D. Taxerås
- Department of Endocrinology and NutritionGermans Trias i Pujol Research InstituteBarcelonaSpain
| | - María Galán
- Institut de Recerca del Hospital de la Santa Creu i Sant Pau‐Programa ICCCBarcelonaSpain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), ISCIIIMadridSpain
| | - Laura Campderros
- Department of Biochemistry and Molecular Biology, Institute of BiomedicineUniversity of BarcelonaBarcelonaSpain
- Biomedical Research Center (Red Fisiopatología de la Obesidad y Nutrición) (CIBEROBN), ISCIIIMadridSpain
| | - Irene Piquer‐Garcia
- Department of Endocrinology and NutritionGermans Trias i Pujol Research InstituteBarcelonaSpain
| | - Silvia Pellitero
- Department of Endocrinology and NutritionGermans Trias i Pujol Research InstituteBarcelonaSpain
- Biomedical Research Center (Red Fisiopatología de la Diabetes y enfermedades metabólicas) (CIBERDEM), ISCIIIMadridSpain
| | - Eva Martínez
- Department of Endocrinology and NutritionGermans Trias i Pujol Research InstituteBarcelonaSpain
| | - Rocío Puig
- Department of Endocrinology and NutritionGermans Trias i Pujol Research InstituteBarcelonaSpain
| | - Icíar Lucena
- Department of Endocrinology and NutritionGermans Trias i Pujol Research InstituteBarcelonaSpain
| | - Jordi Tarascó
- Department of SurgeryGermans Trias i Pujol Research InstituteBarcelonaSpain
| | - Pau Moreno
- Department of SurgeryGermans Trias i Pujol Research InstituteBarcelonaSpain
| | - José Balibrea
- Metabolic and Bariatric Surgery Unit, EAC‐BS Center of ExcellenceVall d'Hebron University HospitalBarcelonaSpain
| | - Joan Bel
- Department of PediatricGermans Trias i Pujol Research InstituteBarcelonaSpain
| | - Marta Murillo
- Department of PediatricGermans Trias i Pujol Research InstituteBarcelonaSpain
| | - María Martínez
- Department of PediatricGermans Trias i Pujol Research InstituteBarcelonaSpain
| | - Marta Ramon‐Krauel
- Endocrinology DepartmentInstitut de Recerca Sant Joan de DéuBarcelonaSpain
- Hospital Sant Joan de DéuBarcelonaSpain
| | - Manel Puig‐Domingo
- Department of Endocrinology and NutritionGermans Trias i Pujol Research InstituteBarcelonaSpain
- Biomedical Research Center (Red Fisiopatología de la Diabetes y enfermedades metabólicas) (CIBERDEM), ISCIIIMadridSpain
| | - Francesc Villarroya
- Department of Biochemistry and Molecular Biology, Institute of BiomedicineUniversity of BarcelonaBarcelonaSpain
- Biomedical Research Center (Red Fisiopatología de la Obesidad y Nutrición) (CIBEROBN), ISCIIIMadridSpain
| | - Carles Lerin
- Endocrinology DepartmentInstitut de Recerca Sant Joan de DéuBarcelonaSpain
- Hospital Sant Joan de DéuBarcelonaSpain
| | - David Sánchez‐Infantes
- Department of Endocrinology and NutritionGermans Trias i Pujol Research InstituteBarcelonaSpain
- Biomedical Research Center (Red Fisiopatología de la Obesidad y Nutrición) (CIBEROBN), ISCIIIMadridSpain
| |
Collapse
|
|
14
|
Integrated Therapeutic Targeting of the Prostate Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1296:183-198. [PMID: 34185293 DOI: 10.1007/978-3-030-59038-3_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/07/2023]
Abstract
Prostate cancer is a common and deadly cancer among men. The heterogeneity that characterizes prostate tumors contributes to clinical challenges in the diagnosis, prognosis, and treatment of this malignancy. While localized prostate cancer can be treated with surgery or radiotherapy, metastatic disease to the lymph nodes and the bone requires aggressive treatment with androgen deprivation treatment (ADT). Unfortunately, this often eventually progresses to metastatic castration-resistant prostate cancer (mCRPC). Advanced prostate cancer treatment today involves 1st- and 2nd-line taxane chemotherapy and 2nd-generation antiandrogens. The process of epithelial mesenchymal transition (EMT), during which epithelial cells lose their adhesions and their polarity, is a critical contributor to prostate cancer metastasis. In this article, we aim to integrate the current understanding of mechanisms dictating the dynamics of phenotypic EMT, with apoptosis outcomes in prostate tumors in response to antiandrogen and taxane chemotherapy for the treatment of advanced disease. Novel insights into the signaling mechanisms that target the functional interface between apoptosis and EMT will be considered in the context of potential clinical markers of tumor prognosis, as well as for effective therapeutic targeting of α- and β- adrenergic signaling (by novel and existing chemotherapeutic agents and antiandrogens). Interfering with EMT and apoptosis simultaneously toward eradicating the tumor mass is of major significance in combating the lethal disease and increasing patient survival.
Collapse
|
|
15
|
Yuan W, Goldstein LD, Durinck S, Chen YJ, Nguyen TT, Kljavin NM, Sokol ES, Stawiski EW, Haley B, Ziai J, Modrusan Z, Seshagiri S. S100a4 upregulation in Pik3caH1047R;Trp53R270H;MMTV-Cre-driven mammary tumors promotes metastasis. Breast Cancer Res 2019; 21:152. [PMID: 31881983 PMCID: PMC6935129 DOI: 10.1186/s13058-019-1238-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 12/06/2019] [Indexed: 11/10/2022] Open
Abstract
Background PIK3CA mutations are frequent in human breast cancer. Pik3caH1047R mutant expression in mouse mammary gland promotes tumorigenesis. TP53 mutations co-occur with PIK3CA mutations in human breast cancers. We previously generated a conditionally activatable Pik3caH1047R;MMTV-Cre mouse model and found a few malignant sarcomatoid (spindle cell) carcinomas that had acquired spontaneous dominant-negative Trp53 mutations. Methods A Pik3caH1047R;Trp53R270H;MMTV-Cre double mutant mouse breast cancer model was generated. Tumors were characterized by histology, marker analysis, transcriptional profiling, single-cell RNA-seq, and bioinformatics. Cell lines were developed from mutant tumors and used to identify and confirm genes involved in metastasis. Results We found Pik3caH1047R and Trp53R270H cooperate in driving oncogenesis in mammary glands leading to a shorter latency than either alone. Double mutant mice develop multiple histologically distinct mammary tumors, including adenocarcinoma and sarcomatoid (spindle cell) carcinoma. We found some tumors to be invasive and a few metastasized to the lung and/or the lymph node. Single-cell RNA-seq analysis of the tumors identified epithelial, stromal, myeloid, and T cell groups. Expression analysis of the metastatic tumors identified S100a4 as a top candidate gene associated with metastasis. Metastatic tumors contained a much higher percentage of epithelial–mesenchymal transition (EMT)-signature positive and S100a4-expressing cells. CRISPR/CAS9-mediated knockout of S100a4 in a metastatic tumor-derived cell line disrupted its metastatic potential indicating a role for S100a4 in metastasis. Conclusions Pik3caH1047R;Trp53R270H;MMTV-Cre mouse provides a preclinical model to mimic a subtype of human breast cancers that carry both PIK3CA and TP53 mutations. It also allows for understanding the cooperation between the two mutant genes in tumorigenesis. Our model also provides a system to study metastasis and develop therapeutic strategies for PIK3CA/TP53 double-positive cancers. S100a4 found involved in metastasis in this model can be a potential diagnostic and therapeutic target.
Collapse
Affiliation(s)
- Wenlin Yuan
- Department of Molecular Biology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Leonard D Goldstein
- Department of Molecular Biology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.,Department of Bioinformatics and Computational Biology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Steffen Durinck
- Department of Molecular Biology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.,Department of Bioinformatics and Computational Biology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Ying-Jiun Chen
- Department of Molecular Biology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Thong T Nguyen
- Department of Molecular Biology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Noelyn M Kljavin
- Department of Cancer Signaling, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Ethan S Sokol
- Foundation Medicine Inc., 150 Second Street, Cambridge, MA, 02141, USA
| | - Eric W Stawiski
- Research and Development Department, MedGenome Inc., Foster City, CA, 94404, USA
| | - Benjamin Haley
- Department of Molecular Biology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA
| | - James Ziai
- Department of Pathology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Zora Modrusan
- Department of Molecular Biology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Somasekar Seshagiri
- Department of Molecular Biology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA. .,SciGenom Research Foundation, Bangalore, 560099, India.
| |
Collapse
|
|
16
|
Yang L, Song L, Ma D, Zhang J, Xie H, Wu H, Liu H, Yu S, Liang H, Zhang P, Cui L, Yuan H, Chen L. Plasma S100A4 level and cardiovascular risk in patients with unstable angina pectoris. Biomark Med 2019; 13:1459-1467. [PMID: 31596125 DOI: 10.2217/bmm-2019-0137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: We investigated whether S100A4 level is associated with pathophysiology of unstable angina pectoris (UAP), and its potential prognostic value for subsequent cardiovascular events. Methods: We compared plasma levels of S100A4 and a set of clinical markers in three groups (59 with UAP, 32 with stable angina pectoris and 30 healthy controls). Results: S100A4 levels in patients with UAP were significantly elevated. In UAP group, baseline S100A4 levels were significantly higher in patients with subsequent cardiovascular events than those without, a positive correlation was identified between the risk of subsequent cardiovascular events and the plasma levels of S100A4. Conclusion: Elevated S100A4 levels may be involved in the pathogenesis of UAP, and may be a marker predictive of post-treatment cardiovascular events.
Collapse
Affiliation(s)
- Le Yang
- Department of Cardiology, Shandong Provincial Hospital affiliated to Shandong University, Shandong, PR China
| | - Liang Song
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, PR China
| | - Danfeng Ma
- Department of Vascular Surgery, Shandong Provincial Hospital affiliated to Shandong University, Shandong, PR China
| | - Jingjing Zhang
- Department of Obstetrics, Weifang Yidu Central Hospital, Shandong, PR China
| | - Hao Xie
- Department of Cardiology, Nanjing Drum Tower Hospital, Jiangsu, PR China
| | - Hongpeng Wu
- Department of Medical Imaging, Shandong Provincial Hospital affiliated to Shandong University, Shandong, PR China
| | - Hang Liu
- Department of Cardiology, The Second Affiliated Hospital of Zhengzhou University, Henan, PR China
| | - Shuang Yu
- Department of Cardiology, Zibo Zhoucun People's Hospital, Shandong, PR China
| | - Hengyi Liang
- Department of Cardiology, Shandong Provincial Hospital affiliated to Shandong University, Shandong, PR China
| | - Pu Zhang
- Department of Cardiology, Taian City Central Hospital, Shandong, PR China
| | - Lianqun Cui
- Department of Cardiology, Shandong Provincial Hospital affiliated to Shandong University, Shandong, PR China
| | - Haitao Yuan
- Department of Cardiology, Shandong Provincial Hospital affiliated to Shandong University, Shandong, PR China
| | - Liming Chen
- Department of Cardiology, Shandong Provincial Hospital affiliated to Shandong University, Shandong, PR China
| |
Collapse
|
|
17
|
Jia F, Liu M, Li X, Zhang F, Yue S, Liu J. Relationship between S100A4 protein expression and pre-operative serum CA19.9 levels in pancreatic carcinoma and its prognostic significance. World J Surg Oncol 2019; 17:163. [PMID: 31526392 PMCID: PMC6747733 DOI: 10.1186/s12957-019-1707-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 09/09/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Pancreatic carcinoma (PC) is one of the most lethal malignancies, and its poor prognosis is strongly associated with invasion and metastasis. CA19.9 is considered to be the most sensitive serum marker for PC in clinical practice; however, the detection of CA19.9 in PC has a certain false positive and false negative rate. The expression of the calcium-binding protein S100A4 has been reported to be associated with poor prognosis in various cancers. This study aimed to investigate the relationship between S100A4 and CA19.9 and its prognostic significance in PC. METHODS We performed immunohistochemical staining for S100A4 in formalin-fixed, paraffin-embedded blocks of 128 PC tissues. The levels of S100A4 expression and pre-operative serum CA19.9 were correlated with clinicopathological parameters. The possible correlation between S100A4 protein expression and pre-operative serum CA19.9 levels were evaluated using the chi-square test and Spearman correlation. Survival was assessed by Kaplan-Meier analysis together with a single variable or multivariate Cox analysis. RESULTS A significant positive correlation between S100A4 expression and pre-operative serum CA19.9 level was observed in PC tissues (ρ = 0.202, P = 0.022). The co-expression of both proteins correlated significantly with tumor differentiation (ρ = - 0.280, P = 0.001), TNM stage (ρ = - 0.389, P = 0.000), and lymph node metastasis (ρ = 0.254, P = 0.008). Upregulation of S100A4 was identified as a significant, independent predictor of poor overall survival (P = 0.000). Moreover, higher serum CA19.9 levels (≥ 35 U/mL) were also recognized as an independent predictor of inferior overall survival (P = 0.001). Additionally, upregulation of S100A4 and higher pre-operative serum CA19.9 levels (≥ 35 U/mL) in patients with PC contributed to a significant decrease in overall survival (P = 0.000). CONCLUSIONS The expression levels of S100A4 in PC tissues were positively correlated with pre-operative serum CA19.9 levels. S100A4 expression and pre-operative serum CA19.9 levels were significant, independent prognostic factors for the overall survival of patients with PC. S100A4 expression/pre-operative serum CA19.9 levels may prove useful as dual prognostic biomarkers for PC. Analysis of CA19.9 in combination with S100A4 can better predict the prognosis of PC.
Collapse
Affiliation(s)
- Fuxin Jia
- Department of Hepato-pancreatico-biliary Surgery, Luo Yang Central Hospital Affiliated to Zheng Zhou University, No. 288 Zhongzhou Middle Road, Luo yang, 471000, Henan Province, China.
| | - Mengmeng Liu
- Infectious Disease Prevention and Control Institute, Luo Yang Center for Disease Control and Prevention, No. 9 Zhenghe Road, Luo yang, 471000, Henan Province, China
| | - Xiao Li
- Department of Hepato-Pancreatico-Biliary Surgery, Xijing Hospital, Air Force Medical University, No.15 Changle West Road, Xi'an, 710032, Shanxi Province, China
| | - Fen Zhang
- Department of Hepato-Pancreatico-Biliary Surgery, Xijing Hospital, Air Force Medical University, No.15 Changle West Road, Xi'an, 710032, Shanxi Province, China
| | - Shuqiang Yue
- Department of Hepato-Pancreatico-Biliary Surgery, Xijing Hospital, Air Force Medical University, No.15 Changle West Road, Xi'an, 710032, Shanxi Province, China
| | - Jiangwei Liu
- Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Command of the PLA, NO. 359 Youhao North Road, Urumuqi, 830000, Xinjiang Uygur Autonomous Region, China
| |
Collapse
|
|
18
|
Abstract
The metastasis-promoting S100A4 protein, a member of the S100 family, has recently been discovered as a potent factor implicated in various inflammation-associated diseases. S100A4 is involved in a range of biological functions such as angiogenesis, cell differentiation, apoptosis, motility, and invasion. Moreover, S100A4 is also a potent trigger of inflammatory processes and induces the release of cytokines and growth factors under different pathological conditions.Indeed, the release of S100A4 upon stress and mainly its pro-inflammatory role emerges as the most decisive activity in disease development, such as rheumatoid arthritis (RA), systemic sclerosis (SSc) allergy, psoriasis, and cancer. In the scope of this review, we will focus on the role of S100A4 as a mediator of pro-inflammatory pathways and its associated biological processes involved in the pathogenesis of various human noncommunicable diseases (NCDs) including cancer.
Collapse
|
|
19
|
Ishikawa M, Osaki M, Yamagishi M, Onuma K, Ito H, Okada F, Endo H. Correlation of two distinct metastasis-associated proteins, MTA1 and S100A4, in angiogenesis for promoting tumor growth. Oncogene 2019; 38:4715-4728. [PMID: 30745574 DOI: 10.1038/s41388-019-0748-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 12/12/2018] [Accepted: 01/29/2019] [Indexed: 01/08/2023]
Abstract
Extensive studies on metastasis-associated proteins, S100A4 and MTA1, have been carried out for over two decades, but correlation of both proteins remains obscure. Here we show evidence for the correlation in angiogenesis. First, silencing of each protein by siRNA-mediated knockdown in mouse endothelial MSS31 cells resulted in the inhibition of tube formation. Unexpectedly, the knockdown of MTA1 affected not only its own expression but also the expression of S100A4, whereas silencing of S100A4 did not affect the MTA1 expression. Additionally, non-muscle myosin IIA (NMIIA) phosphorylation, which was partly controlled by S100A4, was found to be upregulated by knockdown of both proteins in MSS31 cells. Moreover, cycloheximide treatment of MSS31 cells revealed that the rate of S100A4 degradation was accelerated by MTA1 knockdown. This finding, together with our observation that cytoplasmic MTA1, but not nuclear MTA1, was colocalized with S100A4, suggested the involvement of MTA1 in S100A4 stability. The direct in vivo angiogenesis assay showed that both protein siRNAs provoked a significant inhibition of new blood vessel formation induced by angiogenic factors, indicating their anti-angiogenic activities. Treatment of human pancreatic tumor (PANC-1) xenograft in mice with mMTA1 siRNA resulted in tumor regression via suppression of angiogenesis in vivo, as also observed in the case of human prostate cancer xenograft treated with mS100A4 siRNA. Taken together, these data led us to conclude that the MTA1-S100A4-NMIIA axis exists in endothelial cells as a novel pathway in promoting tumor vascular formation and could be a target for suppressing tumor growth and metastasis.
Collapse
Affiliation(s)
- Mizuho Ishikawa
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Mitsuhiko Osaki
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
- Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Makoto Yamagishi
- Laboratory of Tumor Cell Biology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan
| | - Kunishige Onuma
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Hisao Ito
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Futoshi Okada
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
- Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Hideya Endo
- Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan.
| |
Collapse
|
|
20
|
Malpique R, Sánchez-Infantes D, Garcia-Beltran C, Taxerås SD, López-Bermejo A, de Zegher F, Ibáñez L. Towards a circulating marker of hepato-visceral fat excess: S100A4 in adolescent girls with polycystic ovary syndrome - Evidence from randomized clinical trials. Pediatr Obes 2019; 14:e12500. [PMID: 30653851 DOI: 10.1111/ijpo.12500] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 11/29/2018] [Accepted: 12/03/2018] [Indexed: 12/16/2022]
Abstract
S100A4 is a marker of subcutaneous adipose tissue dysfunction. Polycystic ovary syndrome (PCOS) is often driven by hepato-visceral adiposity. PCOS phenotypes are normalized more by reduction of central fat with spironolactone/pioglitazone/metformin (SPIOMET) than by oral contraceptive (OC) treatment. We studied whether circulating S100A4 concentrations are high in adolescents with PCOS and, if so, whether they normalize more with OC or SPIOMET. Assessments included circulating S100A4, endocrine markers, body composition, abdominal fat partitioning in controls (n = 12) and girls with PCOS (n = 51; age 15.8 y; body mass index [BMI] 24.5 kg/m2 ), and 1-year changes in girls with PCOS randomized for OC (n = 27) or SPIOMET (n = 24) treatment. Mean S100A4 concentrations were 71% higher (P < 0.001) in girls with PCOS than in controls and associated with hepato-visceral adiposity (r = 0.47; P = 0.001); S100A4 concentrations decreased more (P < 0.01) with SPIOMET, those decreases associating to hepato-visceral fat loss (r = 0.50; P < 0.0001). S100A4 may become a circulating marker of hepato-visceral fat excess in adolescents with PCOS.
Collapse
Affiliation(s)
- Rita Malpique
- Endocrinology, Pediatric Research Institute Sant Joan de Déu, University of Barcelona, Barcelona, Spain.,Network Biomedical Research Center of Diabetes and Associated Metabolic Disorders (CIBERDEM), Health Institute Carlos III, Madrid, Spain
| | | | - Cristina Garcia-Beltran
- Endocrinology, Pediatric Research Institute Sant Joan de Déu, University of Barcelona, Barcelona, Spain.,Network Biomedical Research Center of Diabetes and Associated Metabolic Disorders (CIBERDEM), Health Institute Carlos III, Madrid, Spain
| | - Siri D Taxerås
- Endocrinology and Nutrition, Germans Trias i Pujol Research Institute, Barcelona, Spain
| | - Abel López-Bermejo
- Pediatric Endocrinology, Hospital Dr. Josep Trueta & Girona Institute for Biomedical Research, Girona, Spain
| | - Francis de Zegher
- Department of Development & Regeneration, University of Leuven, Leuven, Belgium
| | - Lourdes Ibáñez
- Endocrinology, Pediatric Research Institute Sant Joan de Déu, University of Barcelona, Barcelona, Spain.,Network Biomedical Research Center of Diabetes and Associated Metabolic Disorders (CIBERDEM), Health Institute Carlos III, Madrid, Spain
| |
Collapse
|
|
21
|
Yoshimura H, Otsuka A, Michishita M, Yamamoto M, Ashizawa M, Zushi M, Moriya M, Azakami D, Ochiai K, Matsuda Y, Ishiwata T, Kamiya S, Takahashi K. Expression and Roles of S100A4 in Anaplastic Cells of Canine Mammary Carcinomas. Vet Pathol 2019; 56:389-398. [DOI: 10.1177/0300985818823772] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
S100A4 (metastasin), a member of the S100 protein family, was initially identified in metastatic cells and is well established as a marker of aggressive human cancer. However, expression and roles of S100A4 in canine mammary tumors have not been clarified. In this study, expression of S100A4 was examined immunohistochemically in normal, hyperplastic, and neoplastic mammary glands of dogs. In all normal and benign lesions, S100A4 was restricted to a few stromal fibroblasts and inflammatory cells. However, in 7 of 57 (12%) of the malignant tumors examined, cytoplasmic and nuclear expression of S100A4 was observed in epithelial tumor cells and stromal cells. Particularly, the frequency of S100A4-positive anaplastic carcinomas was high (4/8 cases, 50%). Next, we established a novel cell line, named NV-CML, from a S100A4-positive canine mammary carcinoma. The cultured NV-CML cells and the tumors that developed in the immunodeficient mice after subcutaneous injection of the cells maintained the immunophenotype of the original tumor, including S100A4 expression. Using this cell line, we examined the cellular functions of S100A4 using RNA interference. S100A4 expression level in NV-CML cells transfected with small interfering RNA (siRNA) targeting canine S100A4 (siS100A4) was reduced to about one-fifth of those with negative-control siRNA (siNeg). Cell proliferation in WST-8 assay and cell migration in Boyden chamber assay were significantly decreased in siS100A4-transfected cells compared with siNeg-transfected cells. These findings suggest that S100A4 may be related to progression of canine mammary carcinomas via its influence on cell growth and motility.
Collapse
Affiliation(s)
- Hisashi Yoshimura
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Aya Otsuka
- Department of Veterinary Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Masaki Michishita
- Department of Veterinary Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Masami Yamamoto
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Minori Ashizawa
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Manami Zushi
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Maiko Moriya
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Daigo Azakami
- Department of Veterinary Nursing, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Kazuhiko Ochiai
- Department of Basic Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Yoko Matsuda
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
| | - Toshiyuki Ishiwata
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Shinji Kamiya
- Division of Animal Higher Function, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Kimimasa Takahashi
- Department of Veterinary Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan
| |
Collapse
|
|
22
|
Li F, Shi J, Xu Z, Yao X, Mou T, Yu J, Liu H, Li G. S100A4-MYH9 Axis Promote Migration and Invasion of Gastric Cancer Cells by Inducing TGF-β-Mediated Epithelial-Mesenchymal Transition. J Cancer 2018; 9:3839-3849. [PMID: 30410586 PMCID: PMC6218764 DOI: 10.7150/jca.25469] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 07/17/2018] [Indexed: 12/16/2022] Open
Abstract
Driver genes conducing to peritoneal metastasis in advanced gastric cancer remain to be clarified. S100A4 is suggested to evolve in metastasis of gastrointestinal cancer, we aim to explore the role of S100A4 plays in metastasis of advanced gastric cancer and the potential mechanism. Transfection of siRNA or cDNA was applied to alter the expression of protein S100A4 and MYH9, investigation of the expression of epithelial and mesenchymal transition (EMT) associated markers was followed. Cell migration assay was used to screen the alteration of migration ability regulated by S100A4 and MYH9. IHC analysis for tissue sample microarray was performed to reveal their relationship with clinical pathological parameters and potential capacity of predicting survival. Consistent overexpression of S100A4 and MYH9 were found in peritoneal metastasis and primary site compared with adjacent normal tissue. Low expression of S100A4 led to increased epithelial markers as wells as decline of mesenchymal makers, while overexpression of S100A4 led to inverse impact. S100A4 expression was closely correlated with increased migration ability and EMT process induced by TGF-β stimulation. Interference of S100A4 led to downregulation of MYH9 and inactivation of Smad pathway through participating in EMT process, which could be reversed by overexpression of MYH9. Moreover, co-expression of S100A4 and MYH9 was identified in tissue microarray and confirmed by immunofluorescence assay. In conclusion, overexpression of S100A4 and downstream molecular MYH9 in advanced gastric cancer predicted poor prognosis; oncogene S100A4 facilitate EMT process induced by TGF-β stimulation, suggesting a potential target in management of peritoneal metastasis of gastric cancer.
Collapse
Affiliation(s)
- Fengping Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Jiaolong Shi
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Zhijun Xu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Xingxing Yao
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Tingyu Mou
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| |
Collapse
|
|
23
|
S100A4 May Be a Good Prognostic Marker and a Therapeutic Target for Colon Cancer. JOURNAL OF ONCOLOGY 2018; 2018:1828791. [PMID: 30111999 PMCID: PMC6077577 DOI: 10.1155/2018/1828791] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 06/25/2018] [Indexed: 01/05/2023]
Abstract
Background Globally, the colorectal cancers rank the third in terms of cancer incidence and rank the fourth in cancer-associated deaths. S100A4, an important member of the S100 protein family, serves to promote tumor progression and metastasis. By conducting this study, we aim to examine the role of S100A4 in the prognosis of colon cancer and to demonstrate its prognostic significance. Methods Tissue samples of colon cancer from 148 patients who underwent colon resection due to colon cancer were analyzed by immunohistochemical staining to determine the protein expression levels of S100A4. The protein expression levels of S100A4 in tumor tissue were matched with the clinicopathologic factors including patient survival. Results Cytoplasmic expression of S100A4 protein was demonstrated in the tumor tissue of 132 patients (89.2%) out of a total of 148 study patients. Statistically, the expression levels of the cytoplasmic S100A4 protein correlated significantly with the TNM stages and patient survival. The distribution of the S100A4 protein staining in the tumor tissue was associated with the age groups, tumor localization, TNM staging, and patient survival with statistical significance. The levels of S100A4 protein expression were found to be an independent prognostic factor for TNM staging and poor survival. Conclusion Expression of the S100A4 protein in colon cancers may be an indicator of tumor progression and lymph node metastasis and may be useful for predicting the overall survival of the patients with colon cancer. In patients with colon cancer, it may be used as an indicator of poor prognosis.
Collapse
|
|
24
|
Hagiwara S, Sourris K, Ziemann M, Tieqiao W, Mohan M, McClelland AD, Brennan E, Forbes J, Coughlan M, Harcourt B, Penfold S, Wang B, Higgins G, Pickering R, El-Osta A, Thomas MC, Cooper ME, Kantharidis P. RAGE Deletion Confers Renoprotection by Reducing Responsiveness to Transforming Growth Factor-β and Increasing Resistance to Apoptosis. Diabetes 2018; 67:960-973. [PMID: 29449307 DOI: 10.2337/db17-0538] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 02/07/2018] [Indexed: 11/13/2022]
Abstract
Signaling via the receptor of advanced glycation end products (RAGE)-though complex and not fully elucidated in the setting of diabetes-is considered a key injurious pathway in the development of diabetic nephropathy (DN). We report here that RAGE deletion resulted in increased expression of fibrotic markers (collagen I and IV, fibronectin) and the inflammatory marker MCP-1 in primary mouse mesangial cells (MCs) and in kidney cortex. RNA sequencing analysis in MCs from RAGE-/- and wild-type mice confirmed these observations. Nevertheless, despite these gene expression changes, decreased responsiveness to transforming growth factor-β was identified in RAGE-/- mice. Furthermore, RAGE deletion conferred a more proliferative phenotype in MCs and reduced susceptibility to staurosporine-induced apoptosis. RAGE restoration experiments in RAGE-/- MCs largely reversed these gene expression changes, resulting in reduced expression of fibrotic and inflammatory markers. This study highlights that protection against DN in RAGE knockout mice is likely to be due in part to the decreased responsiveness to growth factor stimulation and an antiapoptotic phenotype in MCs. Furthermore, it extends our understanding of the role of RAGE in the progression of DN, as RAGE seems to play a key role in modulating the sensitivity of the kidney to injurious stimuli such as prosclerotic cytokines.
Collapse
Affiliation(s)
- Shinji Hagiwara
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Karly Sourris
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Mark Ziemann
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Wu Tieqiao
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Muthukumar Mohan
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Aaron D McClelland
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Eoin Brennan
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Josephine Forbes
- Mater Clinical School, University of Queensland, St. Lucia, Brisbane, Australia
| | - Melinda Coughlan
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Brooke Harcourt
- Centre for Hormone Research, Murdoch Children's Research Institute, Melbourne, Australia
| | - Sally Penfold
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Bo Wang
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
- Kidney Regeneration and Stem Cell Laboratory, Monash University, Melbourne, Australia
| | - Gavin Higgins
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Raelene Pickering
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Assam El-Osta
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Merlin C Thomas
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Mark E Cooper
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | - Phillip Kantharidis
- Department of Diabetes, Monash University, Melbourne, Australia
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| |
Collapse
|
|
25
|
Dukhanina EA, Lukyanova TI, Dukhanin AS, Georgieva SG. The role of S100A4 protein in anticancer cytotoxicity: its presence is required on the surface of CD 4+CD 25+PGRPs +S100A4 + lymphocyte and undesirable on the surface of target cells. Cell Cycle 2018; 17:479-485. [PMID: 29251175 DOI: 10.1080/15384101.2017.1415678] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
S100A4 is a Ca2+-binding protein that performs an important role in metastasis. It is also known for its antitumor functions. S100A4 is expressed by a specialized subset of CD4+CD25+ lymphocytes and is present on those cell's membranes along with peptidoglycan recognition proteins (PGRPs). There, by interacting with major heat shock protein Hsp70, S100A4 plays an important cytotoxic role. The resulting stably formed complex of PGRPs, S100A4 and Hsp70 is required for the identification and binding between a lymphocyte and a target cell. Here, we investigated the S100A4 functions in CD4+CD25+PGRPs+S100A4+ lymphocyte cytotoxicity against target cells. We demonstrated that those lymphocytes do not form a stable complex with the tumor target cells that themselves have S1004A on their surface. That observation can be explained by our finding that S100A4 precludes the formation of a stable complex between PGRPs, S100A4 (on the lymphocytes' surface), and Hsp70 (on the target cells' surface). The decrease in S100A4 level in CD4+CD25+PGRPs+S100A4+ lymphocytes inhibits their cytotoxic activity, while the addition of S100A4 in the medium restores it. Thus, the resistance of target cells to CD4+CD25+PGRPs+ S100A4+ lymphocyte cytotoxicity depends on their S100A4 expression level and can be countered by S100A4 antibodies.
Collapse
Affiliation(s)
- E A Dukhanina
- a Department of Transcription Factors , Engelhardt Institute of Molecular Biology, Russian Academy of Sciences , Moscow , Russia
| | - T I Lukyanova
- b M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry , Russian Academy of Sciences , Moscow , Russia
| | - A S Dukhanin
- c Department of Molecular Pharmacology and Radiobiology , SBEI HPE "National Research Medical University" , Moscow , Russia
| | - S G Georgieva
- a Department of Transcription Factors , Engelhardt Institute of Molecular Biology, Russian Academy of Sciences , Moscow , Russia
| |
Collapse
|
|
26
|
Fei F, Qu J, Li C, Wang X, Li Y, Zhang S. Role of metastasis-induced protein S100A4 in human non-tumor pathophysiologies. Cell Biosci 2017; 7:64. [PMID: 29204268 PMCID: PMC5702147 DOI: 10.1186/s13578-017-0191-1] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Accepted: 11/20/2017] [Indexed: 12/24/2022] Open
Abstract
S100A4, an important member of the S100 family of proteins, is best known for its significant role in promoting cancer progression and metastasis. In addition to its expression in tumors, upregulation of S100A4 expression has been associated with various non-tumor pathophysiology processes. However, the mechanisms underlying the role of S100A4 remain unclear. Activated “host” cells (fibroblasts, immunocytes, vascular cells, among others) secrete S100A4 into the extracellular space in various non-tumor human disorders, where it executes its biological functions by interacting with intracellular target proteins. However, the exact molecular mechanisms underlying these interactions in different non-tumor pathophysiologies vary, and S100A4 is likely one of the cross-linking factors that acts as common intrinsic constituents of biological mechanisms. Numerous studies have indicated that the S100A4-mediated epithelial–mesenchymal transition plays a vital role in the occurrence and development of various non-tumor pathophysiologies. Epithelial–mesenchymal transition can be categorized into three general subtypes based on the phenotype and function of the output cells. S100A4 regulates tissue fibrosis associated with the type II epithelial–mesenchymal transition via various signaling pathways. Additionally, S100A4 stimulates fibroblasts to secrete fibronectin and collagen, thus forming the structural components of the extracellular matrix (ECM) and stimulating their deposition in tissues, contributing to the formation of a pro-inflammatory niche. Simultaneously, S100A4 enhances the motility of macrophages, neutrophils, and leukocytes and promotes the recruitment and chemotaxis of these inflammatory cells to regulate inflammation and immune functions. S100A4 also exerts a neuroprotective pro-survival effect on neurons by rescuing them from brain injury and participates in angiogenesis by interacting with other target molecules. In this review, we summarize the role of S100A4 in fibrosis, inflammation, immune response, neuroprotection, angiogenesis, and some common non-tumor diseases as well as its possible involvement in molecular pathways and potential clinical value.
Collapse
Affiliation(s)
- Fei Fei
- Nankai University School of Medicine, Nankai University, Tianjin, 300071 People's Republic of China.,Departments of Pathology, Tianjin Union Medical Center, Tianjin, 300121 People's Republic of China
| | - Jie Qu
- Nankai University School of Medicine, Nankai University, Tianjin, 300071 People's Republic of China.,Departments of Pathology, Tianjin Union Medical Center, Tianjin, 300121 People's Republic of China
| | - Chunyuan Li
- Nankai University School of Medicine, Nankai University, Tianjin, 300071 People's Republic of China.,Departments of Pathology, Tianjin Union Medical Center, Tianjin, 300121 People's Republic of China
| | - Xinlu Wang
- Departments of Pathology, Tianjin Union Medical Center, Tianjin, 300121 People's Republic of China.,Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193 People's Republic of China
| | - Yuwei Li
- Departments of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121 People's Republic of China
| | - Shiwu Zhang
- Departments of Pathology, Tianjin Union Medical Center, Tianjin, 300121 People's Republic of China
| |
Collapse
|
|
27
|
A review of S100 protein family in lung cancer. Clin Chim Acta 2017; 476:54-59. [PMID: 29146477 DOI: 10.1016/j.cca.2017.11.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 11/10/2017] [Accepted: 11/12/2017] [Indexed: 02/08/2023]
Abstract
S100 protein family, representing 25 relatively small calcium binding proteins, has been reported to be involved in multiple stages of tumorigenesis and progression. These proteins are considered having potential value to be adopted as novel biomarkers in the detection and accurate prediction of many kinds of tumors, including lung cancer. As the one having the highest morbidity and mortality among all cancers, lung carcinoma is still occult for detection, especially at early stage. S100 proteins take participation in the lung neoplasia through playing intracellular and/or extracellular functions, therefore getting involved in a variety of biological processes such as differentiation, proliferation, and migration. A few members have also been testified to modulate TGF-β/Smad-3 mediated transcriptional activity of target genes involved in tumor promotion. In addition to that, a number of proteins in this family have already been reported to experience an abnormal trend in lung cancer at cell, serum and tissue levels. Thus, S100 proteins may serve as effective biomarkers for suspected or already diagnosed lung cancer patients. In future, S100 protein family might be applied as therapeutic targets in clinical treatment of lung cancer. In this review, we firstly summed up the biological and clinical evidence connecting S100 proteins and lung cancer, which has not been summarized before.
Collapse
|
|
28
|
Wang DT, Chu WH, Sun HM, Ba HX, Li CY. Expression and Functional Analysis of Tumor-Related Factor S100A4 in Antler Stem Cells. J Histochem Cytochem 2017; 65:579-591. [PMID: 28832242 PMCID: PMC5624364 DOI: 10.1369/0022155417727263] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/27/2017] [Indexed: 01/09/2023] Open
Abstract
Annual antler renewal is a stem cell-based epimorphic process driven by antler stem cells (ASCs) resident in antlerogenic periosteum (AP). Antlerogenic periosteal cells express a high level of S100A4, a metastasis-associated protein, which intrigued us to explore what role S100A4 could play in antler regeneration. The present study set out to investigate expression and effects of S100A4 in the ASCs and their progeny. The results showed that not only did cells from the AP express a high level of S100A4, but also the pedicle periosteum and the antler growth center. In the antler growth center, we found S100A4-positive cells were specifically located in blood vessel walls and in vascularized areas. In vitro, recombinant deer S100A4 protein stimulated the proliferation of the AP cells, promoted proliferation, migration and tube formation of human vascular endothelial cells, and enhanced migration of Hela cells, but not AP cells. These findings demonstrated that S100A4 in the ASCs may play a significant role in stimulating angiogenesis, proliferation, but not motility, of ASCs. Deer antlers offer a unique model to explore how rapid cell proliferation with a high level of S100A4 expression is elegantly regulated without becoming cancerous.
Collapse
Affiliation(s)
- Da-tao Wang
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
- State Kay Laboratory for Molecular Biology of Special Economic Animals, Changchun, People’s Republic of China
| | - Wen-hui Chu
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
- State Kay Laboratory for Molecular Biology of Special Economic Animals, Changchun, People’s Republic of China
| | - Hong-mei Sun
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
| | - Heng-xing Ba
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
- State Kay Laboratory for Molecular Biology of Special Economic Animals, Changchun, People’s Republic of China
| | - Chun-yi Li
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
| |
Collapse
|
|
29
|
Fei F, Qu J, Zhang M, Li Y, Zhang S. S100A4 in cancer progression and metastasis: A systematic review. Oncotarget 2017; 8:73219-73239. [PMID: 29069865 PMCID: PMC5641208 DOI: 10.18632/oncotarget.18016] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 05/08/2017] [Indexed: 12/11/2022] Open
Abstract
Metastasis is the leading cause of cancer-related death and directly associates with cancer progression, resistance to anticancer therapy, and poor patient survival. Current efforts focusing on the underlying molecular mechanisms of cancer metastasis attract a special attention to cancer researchers. The epithelial-mesenchymal transition is a complex of molecular program during embryogenesis, inflammation, tissue fibrosis, and cancer progression and metastasis. S100A4, an important member of S100 family proteins, functions to increase the tumor progression and metastasis. The molecular mechanisms of S100A4 involving in the progression and metastasis are diverse in various malignant tumors. Detection of S100A4 expression becomes a promising candidate biomarker in cancer early diagnosis and prediction of cancer metastasis and therefore, S100A4 may be a therapeutic target. This review summarized up to date advancement on the role of S100A4 in human cancer development, progression, and metastasis and the underlying molecular events and then strategies to target S100A4 expression experimentally.
Collapse
Affiliation(s)
- Fei Fei
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, P.R.China
- Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, P.R. China
| | - Jie Qu
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, P.R.China
- Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, P.R. China
| | - Mingqing Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, P.R. China
| | - Yuwei Li
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, P.R. China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, P.R. China
| |
Collapse
|
|
30
|
Inubushi T, Nozawa S, Matsumoto K, Irie F, Yamaguchi Y. Aberrant perichondrial BMP signaling mediates multiple osteochondromagenesis in mice. JCI Insight 2017; 2:90049. [PMID: 28768899 DOI: 10.1172/jci.insight.90049] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 06/23/2017] [Indexed: 01/20/2023] Open
Abstract
Multiple hereditary exostoses (MHE) is characterized by the development of numerous benign bony tumors (osteochondromas). Although it has been well established that MHE is caused by mutations in EXT1 and EXT2, which encode glycosyltransferase essential for heparan sulfate (HS) biosynthesis, the cellular origin and molecular mechanisms of MHE remain elusive. Here, we show that in Ext1 mutant mice, osteochondromas develop from mesenchymal stem cell-like progenitor cells residing in the perichondrium, and we show that enhanced BMP signaling in these cells is the primary signaling defect that leads to osteochondromagenesis. We demonstrate that progenitor cells in the perichondrium, including those in the groove of Ranvier, highly express HS and that Ext1 ablation targeted to the perichondrium results in the development of osteochondromas. Ext1-deficient perichondrial progenitor cells show enhanced BMP signaling and increased chondrogenic differentiation both in vitro and in vivo. Consistent with the functional role for enhanced BMP signaling in osteochondromagenesis, administration of the small molecule BMP inhibitor LDN-193189 suppresses osteochondroma formation in two MHE mouse models. Together, our results demonstrate a role for enhanced perichondrial BMP signaling in osteochondromagenesis in mice, and they suggest the possibility of pharmacological treatment of MHE with BMP inhibitors.
Collapse
|
|
31
|
Trolle C, Ivert P, Hoeber J, Rocamonde-Lago I, Vasylovska S, Lukanidin E, Kozlova EN. Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar. Regen Med 2017. [PMID: 28621171 DOI: 10.2217/rme-2016-0163] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
AIM During development, boundary cap neural crest stem cells (bNCSCs) assist sensory axon growth into the spinal cord. Here we repositioned them to test if they assist regeneration of sensory axons in adult mice after dorsal root avulsion injury. MATERIALS & METHODS Avulsed mice received bNCSC or human neural progenitor (hNP) cell transplants and their contributions to glial scar formation and sensory axon regeneration were analyzed with immunohistochemistry and transganglionic tracing. RESULTS hNPs and bNCSCs form similar gaps in the glial scar, but unlike hNPs, bNCSCs contribute Mts1/S100A4 (calcium-binding protein) expression to the scar and do not assist sensory axon regeneration. CONCLUSION bNCSC transplants contribute nonpermissive Mts1/S100A4-expressing cells to the glial scar after dorsal root avulsion.
Collapse
Affiliation(s)
- Carl Trolle
- Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Patrik Ivert
- Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Jan Hoeber
- Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | | | | | - Eugen Lukanidin
- Department of Molecular Cancer Biology, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Elena N Kozlova
- Department of Neuroscience, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
32
|
Morávková P, Kohoutová D, Vávrová J, Bureš J. S100A4 Protein in Inflammatory Bowel Disease: Results of a Single Centre Prospective Study. ACTA MEDICA (HRADEC KRALOVE) 2017; 60:108-113. [PMID: 29439756 DOI: 10.14712/18059694.2018.2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
INTRODUCTION The aim of our study was to assess association of serum S100A4 protein with ulcerative colitis (UC) and Crohn's disease (CD). METHODS Study included 118 subjects: 93 patients with CD, 16 with UC and 9 controls. In CD group, 20/93 patients had B1 phenotype, 19/93 B2, 20/93 B3 and 34/93 B2 + B3. L1 involvement was present in 15/93, L2 in 14/93 and L3 in 64/93 patients. Serum S100A4 concentration was investigated in peripheral venous blood samples by means of ELISA. RESULTS Serum S100A4 was significantly higher in UC (158.6 ± 56.2 ng/mL), p = 0.019 and in CD (154.4 ± 52.1 ng/mL), p = 0.007 compared to controls (104.8 ± 40.5 ng/mL). No difference in S100A4 was revealed between UC and CD, p > 0.05. Serum S100A4 in each CD subgroup (according to behaviour) was significantly higher compared to controls, p < 0.05. Serum S100A4 was significantly higher in L2 (144.6 ± 44.2 ng/mL), p = 0.041 and in L3 (163.0 ± 52.8 ng/mL), p = 0.002 compared to controls and in L3 compared to L1 (126.9 ± 47.6 ng/mL), p = 0.017. CONCLUSION Association of serum S100A4 protein with UC and CD was confirmed. In CD, disease behaviour did not influence serum concentration of S100A4 protein. In CD, higher levels of serum S100A4 were observed in patients with ileo-colonic and colonic involvement compared to those with isolated small bowel involvement.
Collapse
Affiliation(s)
- Paula Morávková
- Charles University, Faculty of Medicine in Hradec Králové, University Hospital Hradec Králové, 2nd Department of Internal Medicine - Gastroenterology, Hradec Králové, Czech Republic.
| | - Darina Kohoutová
- Charles University, Faculty of Medicine in Hradec Králové, University Hospital Hradec Králové, 2nd Department of Internal Medicine - Gastroenterology, Hradec Králové, Czech Republic
| | - Jaroslava Vávrová
- Charles University, Faculty of Medicine in Hradec Králové, University Hospital Hradec Králové, Institute of Clinical Biochemistry and Diagnostics, Hradec Králové, Czech Republic
| | - Jan Bureš
- Charles University, Faculty of Medicine in Hradec Králové, University Hospital Hradec Králové, 2nd Department of Internal Medicine - Gastroenterology, Hradec Králové, Czech Republic
| |
Collapse
|
|
33
|
|
|
34
|
S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction. Cancers (Basel) 2016; 8:cancers8060059. [PMID: 27331819 PMCID: PMC4931624 DOI: 10.3390/cancers8060059] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 05/27/2016] [Accepted: 06/09/2016] [Indexed: 02/07/2023] Open
Abstract
The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most lethal event during the course of the disease and is directly linked to patient survival, critically limiting successful therapy. This review focuses on our studies of the metastasis-inducing gene S100A4, which we identified as transcriptional target of β-catenin. S100A4 increased migration and invasion in vitro and metastasis in mice. In patient CRC samples, high S100A4 levels predict metastasis and reduced patient survival. Our results link pathways important for tumor progression and metastasis: the Wnt signaling pathway and S100A4, which regulates motility and invasiveness. S100A4 suppression by interdicting Wnt signaling has potential for therapeutic intervention. As proof of principle, we applied S100A4 shRNA systemically and prevented metastasis in mice. Furthermore, we identified small molecule inhibitors from high-throughput screens of pharmacologically active compounds employing an S100A4 promoter-driven reporter. Best hits act, as least in part, via intervening in the Wnt pathway and restricted metastasis in mouse models. We currently translate our findings on restricting S100A4-driven metastasis into clinical practice. The repositioned FDA-approved drug niclosamide, targeting Wnt signaling, is being tested in a prospective phase II clinical trial for treatment of CRC patients. Our assay for circulating S100A4 transcripts in patient blood is used to monitor treatment success.
Collapse
|
|
35
|
Role of S100 Proteins in Colorectal Carcinogenesis. Gastroenterol Res Pract 2016; 2016:2632703. [PMID: 26880885 PMCID: PMC4736765 DOI: 10.1155/2016/2632703] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 11/22/2015] [Accepted: 11/29/2015] [Indexed: 12/25/2022] Open
Abstract
The family of S100 proteins represents 25 relatively small (9-13 kD) calcium binding proteins. These proteins possess a broad spectrum of important intracellular and extracellular functions. Colorectal cancer is the third most common cancer in men (after lung and prostate cancer) and the second most frequent cancer in women (after breast cancer) worldwide. S100 proteins are involved in the colorectal carcinogenesis through different mechanisms: they enable proliferation, invasion, and migration of the tumour cells; furthermore, S100 proteins increase angiogenesis and activate NF-κβ signaling pathway, which plays a key role in the molecular pathogenesis especially of colitis-associated carcinoma. The expression of S100 proteins in the cancerous tissue and serum levels of S100 proteins might be used as a precise diagnostic and prognostic marker in patients with suspected or already diagnosed colorectal neoplasia. Possibly, in the future, S100 proteins will be a therapeutic target for tailored anticancer therapy.
Collapse
|
|
36
|
Thanee M, Loilome W, Techasen A, Namwat N, Boonmars T, Pairojkul C, Yongvanit P. Quantitative changes in tumor-associated M2 macrophages characterize cholangiocarcinoma and their association with metastasis. Asian Pac J Cancer Prev 2015; 16:3043-50. [PMID: 25854403 DOI: 10.7314/apjcp.2015.16.7.3043] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The tumor microenvironment (TME) includes numerous non-neoplastic cells such as leukocytes and fibroblasts that surround the neoplasm and influence its growth. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are documented as key players in facilitating cancer appearance and progression. Alteration of the macrophage (CD68, CD163) and fibroblast (α-SMA, FSP-1) cells in Opisthorchis viverrini (Ov)-induced cholangiocarcinoma (CCA) was here assessed using liver tissues from an established hamster model and from 43 human cases using immunohistochemistry. We further investigated whether M2-activated TAMs influence CCA cell migration ability by wound healing assay and Western blot analysis. Macrophages and fibroblasts change their phenotypes to M2-TAMs (CD68+, CD163+) and CAFs (α-SMA+, FSP-1+), respectively in the early stages of carcinogenesis. Interestingly, a high density of the M2-TAMs CCA in patients is significantly associated with the presence of extrahepatic metastases (p=0.021). Similarly, CD163+ CCA cells are correlated with metastases (p=0.002), and they may be representative of an epithelial-to-mesenchymal transition (EMT) with increased metastatic activity. We further showed that M2-TAM conditioned medium can induce CCA cell migration as well as increase N-cadherin expression (mesenchymal marker). The present work revealed that significant TME changes occur at an early stage of Ov-induced carcinogenesis and that M2-TAMs are key factors contributing to CCA metastasis, possibly via EMT processes.
Collapse
Affiliation(s)
- Malinee Thanee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand E-mail : ;
| | | | | | | | | | | | | |
Collapse
|
|
37
|
Tomcik M, Palumbo-Zerr K, Zerr P, Avouac J, Dees C, Sumova B, Distler A, Beyer C, Cerezo LA, Becvar R, Distler O, Grigorian M, Schett G, Senolt L, Distler JHW. S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis. Ann Rheum Dis 2015; 74:1748-55. [PMID: 24709861 DOI: 10.1136/annrheumdis-2013-204516] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 03/21/2014] [Indexed: 01/26/2023]
Abstract
OBJECTIVES S100A4 is a calcium binding protein with regulatory functions in cell homeostasis, proliferation and differentiation that has been shown to promote cancer progression and metastasis. In the present study, we evaluated the role of S100A4 in fibroblast activation in systemic sclerosis (SSc). METHODS The expression of S100A4 was analysed in human samples, murine models of SSc and in cultured fibroblasts by real-time PCR, immunohistochemistry and western blot. The functional role of S100A4 was evaluated using siRNA, overexpression, recombinant protein and S100A4 knockout (S100A4(-/-)) mice. Transforming growth factor β (TGF-β) signalling was assessed by reporter assays, staining for phosphorylated Smad2/3 and analyses of target genes. RESULTS The expression of S100A4 was increased in SSc skin and in experimental fibrosis in a TGF-β/Smad-dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, knockdown of S100A4 reduced the pro-fibrotic effects of TGF-β and decreased the release of collagen. S100A4(-/-) mice were protected from bleomycin-induced skin fibrosis with reduced dermal thickening, decreased hydroxyproline content and lower myofibroblast counts. Deficiency of S100A4 also ameliorated fibrosis in the tight-skin-1 (Tsk-1) mouse model. CONCLUSIONS We characterised S100A4 as a downstream mediator of the stimulatory effects of TGF-β on fibroblasts in SSc. TGF-β induces the expression of S100A4 to stimulate the release of collagen in SSc fibroblasts and induce fibrosis. Since S100A4 is essentially required for the pro-fibrotic effects of TGF-β and neutralising antibodies against S100A4 are currently evaluated, S100A4 might be a candidate for novel antifibrotic therapies.
Collapse
Affiliation(s)
- Michal Tomcik
- Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic
| | - Katrin Palumbo-Zerr
- Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Pawel Zerr
- Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Jerome Avouac
- Rheumatology A Department, Paris Descartes University, Cochin Hospital, Paris, France
| | - Clara Dees
- Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Barbora Sumova
- Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic
| | - Alfiya Distler
- Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Christian Beyer
- Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Lucie Andres Cerezo
- Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic
| | - Radim Becvar
- Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic
| | - Oliver Distler
- Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital, Zurich, Switzerland
| | - Mariam Grigorian
- Neuro-Oncology Group, Faculty of Health Sciences, Institute of Neuroscience and Pharmacology, Copenhagen University, Copenhagen, Denmark
| | - Georg Schett
- Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Ladislav Senolt
- Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic
| | - Jörg H W Distler
- Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| |
Collapse
|
|
38
|
Che P, Yang Y, Han X, Hu M, Sellers JC, Londono-Joshi AI, Cai GQ, Buchsbaum DJ, Christein JD, Tang Q, Chen D, Li Q, Grizzle WE, Lu YY, Ding Q. S100A4 promotes pancreatic cancer progression through a dual signaling pathway mediated by Src and focal adhesion kinase. Sci Rep 2015; 5:8453. [PMID: 25677816 PMCID: PMC4326725 DOI: 10.1038/srep08453] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 01/15/2015] [Indexed: 12/21/2022] Open
Abstract
S100A4 expression is associated with poor clinical outcomes of patients with pancreatic cancer. The effects of loss or gain of S100A4 were examined in pancreatic cancer cell lines. S100A4 downregulation remarkably reduces cell migration and invasion, inhibits proliferation, and induces apoptosis in pancreatic tumor cells. S100A4 downregulation results in significant cell growth inhibition and apoptosis in response to TGF-β1, supporting a non-canonical role of S100A4 in pancreatic cancer. The role of S100A4 in tumor progression was studied by using an orthotopic human pancreatic cancer xenograft mouse model. Tumor mass is remarkably decreased in animals injected with S100A4-deficient pancreatic tumor cells. P27Kip1 expression and cleaved caspase-3 are increased, while cyclin E expression is decreased, in S100A4-deficient pancreatic tumors in vivo. S100A4-deficient tumors have lower expression of vascular endothelial growth factor, suggesting reduced angiogenesis. Biochemical assays revealed that S100A4 activates Src and focal adhesion kinase (FAK) signaling events, and inhibition of both kinases is required to maximally block the tumorigenic potential of pancreatic cancer cells. These findings support that S100A4 plays an important role in pancreatic cancer progression in vivo and S100A4 promotes tumorigenic phenotypes of pancreatic cancer cells through the Src-FAK mediated dual signaling pathway.
Collapse
Affiliation(s)
- Pulin Che
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Youfeng Yang
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Xiaosi Han
- Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Meng Hu
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jeffery C Sellers
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | - Guo-Qiang Cai
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Donald J Buchsbaum
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - John D Christein
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | - Dongquan Chen
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Qianjun Li
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - William E Grizzle
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Yin Ying Lu
- Center of Therapeutic Research for Hepatocellular Carcinoma, 302 hospital, Beijing, China
| | - Qiang Ding
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| |
Collapse
|
|
39
|
Grum-Schwensen B, Klingelhöfer J, Beck M, Bonefeld CM, Hamerlik P, Guldberg P, Grigorian M, Lukanidin E, Ambartsumian N. S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance. BMC Cancer 2015; 15:44. [PMID: 25884510 PMCID: PMC4335362 DOI: 10.1186/s12885-015-1034-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 01/23/2015] [Indexed: 01/19/2023] Open
Abstract
Background The tumor microenvironment plays a determinative role in stimulating tumor progression and metastasis. Notably, tumor-stroma signals affect the pattern of infiltrated immune cells and the profile of tumor-released cytokines. Among the known molecules that are engaged in stimulating the metastatic spread of tumor cells is the S100A4 protein. S100A4 is known as an inducer of inflammatory processes and has been shown to attract T-cells to the primary tumor and to the pre-metastatic niche. The present study aims to examine the immunomodulatory role of S100A4 in vivo and in vitro and assess the mode of action of 6B12, a S100A4 neutralizing antibody. Methods The therapeutic effect of the 6B12 antibody was evaluated in two different mouse models. First, in a model of spontaneous breast cancer we assessed the dynamics of tumor growth and metastasis. Second, in a model of metastatic niche formation we determined the expression of metastatic niche markers. The levels of cytokine expression were assessed using antibody as well as PCR arrays and the results confirmed by qRT-PCR and ELISA. T-cell phenotyping and in vitro differentiation analyses were performed by flow cytometry. Results We show that the S100A4 protein alters the expression of transcription factor and signal transduction pathway genes involved in the T-cell lineage differentiation. T-cells challenged with S100A4 demonstrated reduced proportion of Th1-polarized cells shifting the Th1/Th2 balance towards the Th2 pro-tumorigenic phenotype. The 6B12 antibody restored the Th1/Th2 balance. Furthermore, we provide evidence that the 6B12 antibody deploys its anti-metastatic effect, by suppressing the attraction of T-cells to the site of primary tumor and pre-metastatic niche. This was associated with delayed primary tumor growth, decreased vessel density and inhibition of metastases. Conclusion The S100A4 blocking antibody (6B12) reduces tumor growth and metastasis in a model of spontaneous breast cancer. The 6B12 antibody treatment inhibits T cell accumulation at the primary and pre-metastatic tumor sites. The 6B12 antibody acts as an immunomodulatory agent and thus supports the view that the 6B12 antibody is a promising therapeutic candidate to fight cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1034-2) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
| | - Jörg Klingelhöfer
- Institute of Neuroscience and Pharmacology, Faculty of Health Sciences, Copenhagen University, 2200, Copenhagen, Denmark.
| | - Mette Beck
- Danish Cancer Society Research Center, 2100, Copenhagen, Denmark.
| | - Charlotte Menné Bonefeld
- Institute of International Health, Immunology and Microbiology, Faculty of Health Sciences, Copenhagen University, 2200, Copenhagen, Denmark.
| | - Petra Hamerlik
- Danish Cancer Society Research Center, 2100, Copenhagen, Denmark.
| | - Per Guldberg
- Danish Cancer Society Research Center, 2100, Copenhagen, Denmark.
| | - Mariam Grigorian
- Institute of Neuroscience and Pharmacology, Faculty of Health Sciences, Copenhagen University, 2200, Copenhagen, Denmark.
| | - Eugene Lukanidin
- Danish Cancer Society Research Center, 2100, Copenhagen, Denmark.
| | - Noona Ambartsumian
- Institute of Neuroscience and Pharmacology, Faculty of Health Sciences, Copenhagen University, 2200, Copenhagen, Denmark.
| |
Collapse
|
|
40
|
Pleštilová L, Mann H, Andrés Cerezo L, Pecha O, Vencovský J, Šenolt L. The metastasis promoting protein S100A4 levels associate with disease activity rather than cancer development in patients with idiopathic inflammatory myopathies. Arthritis Res Ther 2014; 16:468. [PMID: 25359220 PMCID: PMC4241220 DOI: 10.1186/s13075-014-0468-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 10/14/2014] [Indexed: 01/20/2023] Open
Abstract
Introduction The aim was to evaluate S100A4 protein as a biomarker of disease activity and potential cancer development in patients with myositis. Methods Serum levels of S100A4 were determined in 43 dermatomyositis (DM), 39 polymyositis (PM) and 22 cancer associated myositis (CAM) patients as well as in 77 healthy controls. The associations between S100A4 levels, inflammation, disease activity, muscle strength and cancer development were evaluated. Results All myositis patients had significantly higher serum levels of S100A4 protein compared to healthy controls (median (IQR): 31.5 (17.4 to 59.5) versus 23.8 (14.5 to 33.7) ng/ml, P <0.05). In patients with PM, serum levels of S100A4 protein were significantly higher than in healthy controls (41.6 (24.2 to 123.1) versus 23.8 (14.5 to 33.7) ng/ml; P <0.001) as well as in patients with DM (26.7 (11.3 to 47.5) ng/ml; P <0.05). The levels of S100A4 were comparable between myositis with and without cancer. In all myositis patients, serum S100A4 levels correlated with MYOsitis disease ACTivity assessment (MYOACT) score (r = 0.34; P = 0.001), constitutional (r = 0.30; P = 0.003), pulmonary (r = 0.43; P = 0.0001) and extramuscular disease activity (r = 0.36; P = 0.0001), as well as with creatine phosphokinase (r = 0.27; P = 0.015) and lactate dehydrogenase (r = 0.37; P = 0.002) or c-reactive protein (CRP) levels (r = 0.24; P = 0.038). Multiple regression analysis showed significant association between S100A4 serum levels and extramuscular disease activity (β = 0.552; P = 0.002) in PM patients and with MYOACT (β = 0.557; P = 0.003) and CRP levels (β = 0.391; P = 0.029) in DM patients. Conclusions Circulating levels of S100A4 are elevated in patients with myositis and associate with several disease activity parameters, particularly with extramuscular components. No relation between S100A4 levels and presence of cancer associated myositis was found. Electronic supplementary material The online version of this article (doi:10.1186/s13075-014-0468-2) contains supplementary material, which is available to authorized users.
Collapse
|
|
41
|
Yuan TM, Liang RY, Hsiao NW, Chuang SM. The S100A4 D10V polymorphism is related to cell migration ability but not drug resistance in gastric cancer cells. Oncol Rep 2014; 32:2307-18. [PMID: 25310523 PMCID: PMC4240476 DOI: 10.3892/or.2014.3540] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 08/21/2014] [Indexed: 01/16/2023] Open
Abstract
Upregulation of the metastasis-promoting S100A4 protein has been linked to tumor migration and invasion, and clinical studies have demonstrated that significant expression of S100A4 in primary tumors is indicative of poor prognosis. However, the involvement of S100A4 in the drug responsiveness of gastric cancer remains unclear. In the present study, we used gastric cancer cell lines as a model to investigate the involvement of S100A4 in drug responsiveness. We overexpressed S100A4 in AGS and SCM-1 cells, which are characterized by relatively low-level expression of endogenous S100A4, and found that this significantly enhanced cell migration but did not affect cell survival in the presence of six common anticancer drugs. Moreover, in vitro cell proliferation was unchanged. Using RNA interference, we suppressed S100A4 expression in MKN-45 and TMK-1 cells (which are characterized by high-level expression of endogenous S100A4), and found that knockdown of S100A4 markedly attenuated cell motility but did not affect cell survival in the presence of six common anticancer drugs. Further study revealed that a single nucleotide polymorphism (SNP) of S100A4 (rs1803245; c.29A>T), which substitutes an Asp residue with Val (D10V), is localized within the conserved binding surface for Annexin II. Cells overexpressing S100A4D10V showed a significant reduction in cell migration ability, but no change in cell survival, upon anticancer drug treatment. Taken together, our novel results indicate that the expression level of S100A4 does not significantly affect cell survival following anticancer drug treatment. Thus, depending on the cell context, the metastasis-promoting effects of S100A4 may not be positively correlated with anticancer drug resistance in the clinic.
Collapse
Affiliation(s)
- Tein-Ming Yuan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C
| | - Ruei-Yue Liang
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C
| | - Nai-Wan Hsiao
- Institute of Biotechnology, National Changhua University of Education, Changhua 50007, Taiwan, R.O.C
| | - Show-Mei Chuang
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C
| |
Collapse
|
|
42
|
Fahrenbach JP, Andrade J, McNally EM. The CO-Regulation Database (CORD): a tool to identify coordinately expressed genes. PLoS One 2014; 9:e90408. [PMID: 24599084 PMCID: PMC3944024 DOI: 10.1371/journal.pone.0090408] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Accepted: 02/01/2014] [Indexed: 02/03/2023] Open
Abstract
Background Meta-analysis of gene expression array databases has the potential to reveal information about gene function. The identification of gene-gene interactions may be inferred from gene expression information but such meta-analysis is often limited to a single microarray platform. To address this limitation, we developed a gene-centered approach to analyze differential expression across thousands of gene expression experiments and created the CO-Regulation Database (CORD) to determine which genes are correlated with a queried gene. Results Using the GEO and ArrayExpress database, we analyzed over 120,000 group by group experiments from gene microarrays to determine the correlating genes for over 30,000 different genes or hypothesized genes. CORD output data is presented for sample queries with focus on genes with well-known interaction networks including p16 (CDKN2A), vimentin (VIM), MyoD (MYOD1). CDKN2A, VIM, and MYOD1 all displayed gene correlations consistent with known interacting genes. Conclusions We developed a facile, web-enabled program to determine gene-gene correlations across different gene expression microarray platforms. Using well-characterized genes, we illustrate how CORD's identification of co-expressed genes contributes to a better understanding a gene's potential function. The website is found at http://cord-db.org.
Collapse
Affiliation(s)
- John P. Fahrenbach
- Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America
- * E-mail:
| | - Jorge Andrade
- Center for Research Informatics, The University of Chicago, Chicago, Illinois, United States of America
| | - Elizabeth M. McNally
- Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America
- Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America
| |
Collapse
|
|
43
|
A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4. Oncogene 2014; 34:424-35. [PMID: 24469032 DOI: 10.1038/onc.2013.568] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Revised: 12/06/2013] [Accepted: 12/07/2013] [Indexed: 12/30/2022]
Abstract
S100A4 is implicated in metastasis and chronic inflammation, but its function remains uncertain. Here we establish an S100A4-dependent link between inflammation and metastatic tumor progression. We found that the acute-phase response proteins serum amyloid A (SAA) 1 and SAA3 are transcriptional targets of S100A4 via Toll-like receptor 4 (TLR4)/nuclear factor-κB signaling. SAA proteins stimulated the transcription of RANTES (regulated upon activation normal T-cell expressed and presumably secreted), G-CSF (granulocyte-colony-stimulating factor) and MMP2 (matrix metalloproteinase 2), MMP3, MMP9 and MMP13. We have also shown for the first time that SAA stimulate their own transcription as well as that of proinflammatory S100A8 and S100A9 proteins. Moreover, they strongly enhanced tumor cell adhesion to fibronectin, and stimulated migration and invasion of human and mouse tumor cells. Intravenously injected S100A4 protein induced expression of SAA proteins and cytokines in an organ-specific manner. In a breast cancer animal model, ectopic expression of SAA1 or SAA3 in tumor cells potently promoted widespread metastasis formation accompanied by a massive infiltration of immune cells. Furthermore, coordinate expression of S100A4 and SAA in tumor samples from colorectal carcinoma patients significantly correlated with reduced overall survival. These data show that SAA proteins are effectors for the metastasis-promoting functions of S100A4, and serve as a link between inflammation and tumor progression.
Collapse
|
|
44
|
Ochiya T, Takenaga K, Endo H. Silencing of S100A4, a metastasis-associated protein, in endothelial cells inhibits tumor angiogenesis and growth. Angiogenesis 2014; 17:17-26. [PMID: 23929008 PMCID: PMC3898373 DOI: 10.1007/s10456-013-9372-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 07/22/2013] [Indexed: 01/28/2023]
Abstract
Endothelial cells express S100A4, a metastasis-associated protein, but its role in angiogenesis remains to be elucidated. Here we show that knockdown of S100A4 in mouse endothelial MSS31 cells by murine specific small interference RNA (mS100A4 siRNA) markedly suppressed capillary-like tube formation in vitro, in early stage after the treatment, along with down- and up-regulation of some of the pro-angiogenic and anti-angiogenic gene expression, respectively. Of particular note is that intra-tumor administration of the mS100A4 siRNA in a human prostate cancer xenograft significantly reduced tumor vascularity and resulted in the inhibition of tumor growth. These findings show that S100A4 in endothelial cells is involved in tube formation, and suggest its potential as a molecular target for inhibiting tumor angiogenesis, which warrants further development of endothelial S100A4-based strategies for cancer treatment.
Collapse
Affiliation(s)
- Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045 Japan
| | - Keizo Takenaga
- Department of Life Science, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo, 693-8501 Japan
| | - Hideya Endo
- Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 Japan
| |
Collapse
|
|
45
|
Siddique HR, Adhami VM, Parray A, Johnson JJ, Siddiqui IA, Shekhani MT, Murtaza I, Ambartsumian N, Konety BR, Mukhtar H, Saleem M. The S100A4 Oncoprotein Promotes Prostate Tumorigenesis in a Transgenic Mouse Model: Regulating NFκB through the RAGE Receptor. Genes Cancer 2013; 4:224-34. [PMID: 24069509 DOI: 10.1177/1947601913492420] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Accepted: 05/11/2013] [Indexed: 01/11/2023] Open
Abstract
S100A4, a calcium-binding protein, is known for its role in the metastatic spread of tumor cells, a late event of cancer disease. This is the first report showing that S100A4 is not merely a metastatic protein but also an oncoprotein that plays a critical role in the development of tumors. We earlier showed that S100A4 expression progressively increases in prostatic tissues with the advancement of prostate cancer (CaP) in TRAMP, an autochthonous mouse model. To study the functional significance of S100A4 in CaP, we generated a heterozygously deleted S100A4 (TRAMP/S100A4(+/-)) genotype by crossing TRAMP with S100A4(-/-) mice. TRAMP/S100A4(+/-) did not show a lethal phenotype, and transgenes were functional. As compared to age-matched TRAMP littermates, TRAMP/S100A4(+/-) mice exhibited 1) an increased tumor latency period (P < 0.001), 2) a 0% incidence of metastasis, and 3) reduced prostatic weights (P < 0.001). We generated S100A4-positive clones from S100A4-negative CaP cells and tested their potential. S100A4-positive tumors grew at a faster rate than S100A4-negative tumors in vitro and in a xenograft mouse model. The S100A4 protein exhibited growth factor-like properties in multimode (intracellular and extracellular) forms. We observed that 1) the growth-promoting effect of S100A4 is due to its activation of NFκB, 2) S100A4-deficient tumors exhibit reduced NFκB activity, 3) S100A4 regulates NFκB through the RAGE receptor, and 4) S100A4 and RAGE co-localize in prostatic tissues of mice. Keeping in view its growth-promoting role, we suggest that S100A4 qualifies as an excellent candidate to be exploited for therapeutic agents to treat CaP in humans.
Collapse
|
|
46
|
Anti-S100A4 antibody suppresses metastasis formation by blocking stroma cell invasion. Neoplasia 2013; 14:1260-8. [PMID: 23308057 DOI: 10.1593/neo.121554] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 10/31/2012] [Accepted: 11/01/2012] [Indexed: 12/24/2022] Open
Abstract
The small Ca-binding protein, S100A4, has a well-established metastasis-promoting activity. Moreover, its expression is tightly correlated with poor prognosis in patients with numerous types of cancer. Mechanistically, the extracellular S100A4 drives metastasis by affecting the tumor microenvironment, making it an attractive target for anti-cancer therapy. In this study, we produced a function-blocking anti-S100A4 monoclonal antibody with metastasis-suppressing activity. Antibody treatment significantly reduced metastatic burden in the lungs of experimental animals by blocking the recruitment of T cells to the site of the primary tumor. In vitro studies demonstrated that this antibody efficiently reduced the invasion of T cells in a fibroblast monolayer. Moreover, it was capable of suppressing the invasive growth of human and mouse fibroblasts. We presume therefore that the antibody exerts its activity by suppressing stroma cell recruitment to the site of the growing tumor. Our epitope mapping studies suggested that the antibody recognition site overlaps with the target binding interface of human S100A4. We conclude here that this antibody could serve as a solid basis for development of an efficient anti-metastatic therapy.
Collapse
|
|
47
|
Chang FC, Chou YH, Chen YT, Lin SL. Novel insights into pericyte-myofibroblast transition and therapeutic targets in renal fibrosis. J Formos Med Assoc 2012; 111:589-98. [PMID: 23217594 DOI: 10.1016/j.jfma.2012.09.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Revised: 09/03/2012] [Accepted: 09/10/2012] [Indexed: 12/31/2022] Open
Abstract
Renal fibrosis is a disease affecting millions worldwide and is a harbinger of progressive renal failure. Understanding the mechanisms of renal fibrosis is important for discovering new therapies that are required to prevent loss of renal function. Recently, we identified pericytes that line the kidney microvasculature as the precursor cells of the scar-producing myofibroblasts during kidney injury. Kidney pericytes are extensively branched cells embedded within the capillary basement membrane and stabilize the capillary network through tissue inhibitor of metalloproteinase 3 and angiogenic growth factors. Pericytes detach from endothelial cells and migrate into the interstitial space where they undergo a transition into myofibroblasts after injury. Activation of endothelium, pericyte-myofibroblast transition, and recruitment of inflammatory macrophages lead to capillary rarefaction and fibrosis. Targeting endothelium-pericyte crosstalk by inhibiting vascular endothelial cell growth factor receptors and platelet-derived growth factor receptors in response to injury have been identified as new therapeutic interventions. Furthermore, targeting macrophage activation has also been proven as a novel and safe therapeutic approach for pericyte-myofibroblast transition. However, we are still far from understanding the interaction between pericytes and other cellular elements in normal physiology and during kidney fibrosis. Further studies will be required to translate into more specific therapeutic approaches.
Collapse
Affiliation(s)
- Fan-Chi Chang
- Renal Division, Department of Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | | | | | | |
Collapse
|
|
48
|
Mishra SK, Siddique HR, Saleem M. S100A4 calcium-binding protein is key player in tumor progression and metastasis: preclinical and clinical evidence. Cancer Metastasis Rev 2012; 31:163-72. [PMID: 22109080 DOI: 10.1007/s10555-011-9338-4] [Citation(s) in RCA: 133] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The fatality of cancer is mainly bestowed to the property of otherwise benign tumor cells to become malignant and invade surrounding tissues by circumventing normal tissue barriers through a process called metastasis. S100A4 which is a member of the S100 family of calcium-binding proteins has been shown to be able to activate and integrate pathways both intracellular and extracellular to generate a phenotypic response characteristic of cancer metastasis. A large number of studies have shown an increased expression level of S100A4 in various types of cancers. However, its implications in cancer metastasis in terms of whether an increased expression of S100A4 is a causal factor for metastasis or just another after effect of several other physiological and molecular changes in the body resulting from metastasis are not clear. Here we describe the emerging preclinical and clinical evidences implicating S100A4 protein, in both its forms (intracellular and extracellular) in the process of tumorigenesis and metastasis in humans. Based on studies utilizing S100A4 as a metastasis biomarker and molecular target for therapies such as gene therapy, we suggest that S100A4 has emerged as a promising molecule to be tested for anticancer drugs. This review provides an insight in the (1) molecular mechanisms through which S100A4 drives the tumorigenesis and metastasis and (2) developments made in the direction of evaluating S100A4 as a cancer biomarker and drug target.
Collapse
Affiliation(s)
- Shrawan Kumar Mishra
- Department of Molecular Chemoprevention and Therapeutics, University of Minnesota, Austin, MN 55912, USA
| | | | | |
Collapse
|
|
49
|
Chai J, Jamal MM. S100A4 in esophageal cancer: Is this the one to blame? World J Gastroenterol 2012; 18:3931-5. [PMID: 22912541 PMCID: PMC3419987 DOI: 10.3748/wjg.v18.i30.3931] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 06/15/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Metastasis is the main reason for cancer-related death. S100A4 is one of the key molecules involved in this event. Several studies have shown that overexpression of S100A4 in non-metastatic cancer cells can make them become metastatic, and knockdown of S100A4 in metastatic cancer cells can curtail their invasive nature. A study by Chen et al[2] published in the World J Gastroenterol 18(9): 915-922, 2012 is a typical example. This study showed in vitro and in vivo evidence that S100A4 expression level determines the invasiveness of esophageal squamous carcinoma. Considering the fact that more than half of the cancer-related deaths are caused by malignancies derived from the digestive system and esophageal cancer is the 4th top contributor to this fraction, this study warrants more attention.
Collapse
|
|
50
|
Lukanidin E, Sleeman JP. Building the niche: the role of the S100 proteins in metastatic growth. Semin Cancer Biol 2012; 22:216-25. [PMID: 22381352 DOI: 10.1016/j.semcancer.2012.02.006] [Citation(s) in RCA: 120] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Accepted: 02/14/2012] [Indexed: 12/30/2022]
Abstract
Communication between cancer cells and stromal cells, often mediated by extracellular molecules in the tumor microenvironment, plays a central role in tumorigenesis and metastasis. The establishment of a pro-inflammatory milieu is increasingly recognized as an important consequence of these interactions. The family of S100 Ca2+-binding proteins has been implicated in many aspects of the interaction between cancer cells and stromal cells, and contributes to the formation of an inflammatory tumor microenvironment. Focusing on S100A4, S100A8 and S100A9, in this review we discuss the role these proteins play in primary tumors and in the development of metastases, in particular during the formation of pre-metastatic niches.
Collapse
Affiliation(s)
- Eugene Lukanidin
- Department of Tumor Microenvironment and Metastasis, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen, 2100, Denmark.
| | | |
Collapse
|