Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2023

Open Access 01-12-2023 | Gastric Cancer | Research

SALL4 promotes angiogenesis in gastric cancer by regulating VEGF expression and targeting SALL4/VEGF pathway inhibits cancer progression

Authors: Fatma A. Abouelnazar, Xiaoxin Zhang, Jiahui Zhang, Maoye Wang, Dan Yu, Xueyan Zang, Jiayin Zhang, Yixin Li, Jing Xu, Qiurong Yang, Yue Zhou, Haozhou Tang, Yanzheng Wang, Jianmei Gu, Xu Zhang

Published in: Cancer Cell International | Issue 1/2023

Login to get access

Abstract

Background

Spalt-like protein 4 (SALL4) is a stemness-related transcription factor whose abnormal re-expression contributes to cancer initiation and progression. However, the role of SALL4 in cancer angiogenesis remains unknown.

Methods

Analyses of clinical specimens via TCGA datasets were performed to determine the expression level and clinical significance of SALL4 in STAD (Stomach Adenocarcinoma). SALL4 knockdown, knockout, and overexpression were achieved by siRNA, CRISPR/Cas9, and plasmid transfection. The effects of conditioned medium (CM) from SALL4 knockdown or overexpression of gastric cancer cells on endothelial cell proliferation, migration, and tube formation were investigated by CCK-8 assay, transwell migration assay, and tube formation assay. The regulation of VEGF gene expression by SALL4 was studied by qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assay, and electrophoretic mobility shift assay (EMSA). Engineered exosomes from 293T cells loaded with si-SALL4-B and thalidomide were produced to test their therapeutic effect on gastric cancer progression.

Results

SALL4 expression was increased in STAD and positively correlated with tumor progression and poor prognosis. SALL4-B knockdown or knockout decreased while over-expression increased the promotion of human umbilical vein endothelial cells (HUVEC) cell proliferation, migration, and tube formation by gastric cancer cell-derived CM. Further investigation revealed a widespread association of SALL4 with angiogenic gene transcription through the TCGA datasets. Additionally, SALL4-B knockdown reduced, while over-expression enhanced the expression levels of VEGF-A, B, and C genes. The results of ChIP and EMSA assays indicated that SALL4 could directly bind to the promoters of VEGF-A, B, and C genes and activate their transcription, which may be associated with increased histone H3-K79 and H3-K4 modifications in their promoter regions. Furthermore, si-SALL4-B and thalidomide-loaded exosomes could be efficiently uptaken by gastric cancer cells and significantly reduced SALL4-B and Vascular Endothelial Growth Factor (VEGF) expression levels in gastric cancer cells, thus inhibiting the pro-angiogenic role of their derived CM.

Conclusion

These findings suggest that SALL4 plays an important role in angiogenesis by transcriptionally regulating VEGF expression. Co-delivery of the functional siRNA and anticancer drug via exosomes represents a useful approach to inhibiting cancer angiogenesis by targeting SALL4/VEGF pathway.
Appendix
Available only for authorised users
Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel L, Torre A, Ahmedin D. GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Global cancer statistics 2018 2018.
2.
Rawla P, Barsouk A. Epidemiology of gastric cancer: global trends, risk factors, and prevention. Gastroenterol Review/PrzeglÄ d Gastroenterologiczny. 2019;14(1):26–38.
3.
Sitarz R, Skierucha M, Mielko J, Offerhaus G, Maciejewski R, Polkowski W. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res. 2018; 10: 239–48. In. Cancer Manag Res; 2018.
4.
5.
Cats A, Jansen EP, van Grieken NC, Sikorska K, Lind P, Nordsmark M, Kranenbarg EM-K, Boot H, Trip AK, Swellengrebel HM. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomized phase 3 trial. Lancet Oncol. 2018;19(5):616–28.PubMedCrossRef
6.
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. nature 2000, 407(6801):249–257.
7.
Burstein HJ, Schwartz RS. Molecular origins of cancer. In., vol. 358: Mass Medical Soc; 2008: 527–527.
8.
Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219(4587):983–5.PubMedCrossRef
9.
Jussila L, Alitalo K. Vascular growth factors and lymphangiogenesis. Physiol Rev. 2002;82(3):673–700.PubMedCrossRef
10.
Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci. 2005;109(3):227–41.CrossRef
11.
Zhang L, Xu Z, Xu X, Zhang B, Wu H, Wang M, Zhang X, Yang T, Cai J, Yan Y, et al. SALL4, a novel marker for human gastric carcinogenesis and metastasis. Oncogene. 2014;33(48):5491–500.PubMedCrossRef
12.
Gonzalez-Roibon N, Katz B, Chaux A, Sharma R, Munari E, Faraj SF, Illei PB, Torbenson M, Netto GJ. Immunohistochemical expression of SALL4 in hepatocellular carcinoma, a potential pitfall in the differential diagnosis of yolk sac tumors. Hum Pathol. 2013;44(7):1293–9.PubMedCrossRef
13.
Li A, Jiao Y, Yong KJ, Wang F, Gao C, Yan B, Srivastava S, Lim GSD, Tang P, Yang H, et al. SALL4 is a new target in endometrial cancer. Oncogene. 2015;34(1):63–72.PubMedCrossRef
14.
Zhang X, Zhang P, Shao M, Zang X, Zhang J, Mao F, Qian H, Xu W. SALL4 activates TGF-β/SMAD signaling pathway to induce EMT and promote gastric cancer metastasis. Cancer Manage Res. 2018;10:4459–70.CrossRef
15.
Liu L, Zhang J, Yang X, Fang C, Xu H, Xi X. SALL4 as an epithelial-mesenchymal transition and Drug Resistance Inducer through the regulation of c-Myc in Endometrial Cancer. PLoS ONE. 2015;10(9):e0138515–5.PubMedPubMedCentralCrossRef
16.
Kim J, Xu S, Xiong L, Yu L, Fu X, Xu Y. SALL4 promotes glycolysis and chromatin remodeling via modulating HP1α-Glut1 pathway. Oncogene. 2017;36(46):6472–9.PubMedCrossRef
17.
Uez N, Lickert H, Kohlhase J, de Angelis MH, Kühn R, Wurst W, Floss T. Sall4 isoforms act during proximal-distal and anterior-posterior axis formation in the mouse embryo. Genesis (New York NY: 2000). 2008;46(9):463–77.CrossRef
18.
Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 2011;17(11):1359–70.PubMedCrossRef
19.
Yong KJ, Li A, Ou W-B, Hong CKY, Zhao W, Wang F, Tatetsu H, Yan B, Qi L, Fletcher JA, et al. Targeting SALL4 by entinostat in lung cancer. Oncotarget. 2016;7(46):75425–40.PubMedPubMedCentralCrossRef
20.
Jiang G, Liu C-T. Knockdown of SALL4 overcomes cisplatin-resistance through AKT/mTOR signaling in lung cancer cells. Int J Clin Exp Pathol. 2018;11(2):634–41.PubMedPubMedCentral
21.
Donovan KA, An J, Nowak RP, Yuan JC, Fink EC, Berry BC, Ebert BL, Fischer ES. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife. 2018;7:e38430.PubMedPubMedCentralCrossRef
22.
Rao S, Zhen S, Roumiantsev S, McDonald LT, Yuan G-C, Orkin SH. Differential roles of Sall4 isoforms in embryonic stem cell pluripotency. Mol Cell Biol. 2010;30(22):5364–80.PubMedPubMedCentralCrossRef
23.
Tammela T, Enholm B, Alitalo K, Paavonen K. The biology of vascular endothelial growth factors. Cardiovascular Res. 2005;65(3):550–63.CrossRef
24.
Yoshiji H, Harris SR, Thorgeirsson UP. Vascular endothelial growth factor is essential for initial but not continued in vivo growth of human breast carcinoma cells. Cancer Res. 1997;57(18):3924–8.PubMed
25.
Giavazzi R, Sennino B, Coltrini D, Garofalo A, Dossi R, Ronca R, Tosatti MPM, Presta M. Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis. Am J Pathol. 2003;162(6):1913–26.PubMedPubMedCentralCrossRef
26.
Sun J, Zhao Z, Zhang W, Tang Q, Yang F, Hu X, Liu C, Song B, Zhang B, Wang H. Spalt-Like protein 4 (SALL4) promotes angiogenesis by activating vascular endothelial growth factor A (VEGFA) signaling. Med Sci Monit. 2020;26:e920851–1.PubMedPubMedCentral
27.
Sun J, Tang Q, Gao Y, Zhang W, Zhao Z, Yang F, Hu X, Zhang D, Wang Y, Zhang H. VHL mutation-mediated SALL4 overexpression promotes tumorigenesis and vascularization of clear cell renal cell carcinoma via Akt/GSK-3β signaling. J Experimental Clin Cancer Res. 2020;39:1–17.CrossRef
28.
Chen T, Tsang JY, Su XC, Li P, Sun WQ, Wong IL, Choy KY, Yang Q, Tse GM, Chan TH. SALL4 promotes tumor progression in breast cancer by targeting EMT. Mol Carcinog. 2020;59(10):1209–26.PubMedCrossRef
29.
Yuan X, Zhang X, Zhang W, Liang W, Zhang P, Shi H, Zhang B, Shao M, Yan Y, Qian H, et al. SALL4 promotes gastric cancer progression through activating CD44 expression. Oncogenesis. 2016;5(11):e268–8.PubMedPubMedCentralCrossRef
30.
Yang J, Chai L, Liu F, Fink LM, Lin P, Silberstein LE, Amin HM, Ward DC, Ma Y. Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proc Natl Acad Sci USA. 2007;104(25):10494–9.PubMedPubMedCentralCrossRef
31.
Li A, Yang Y, Gao C, Lu J, Jeong H-W, Liu BH, Tang P, Yao X, Neuberg D, Huang G, et al. A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis. J Clin Invest. 2013;123(10):4195–207.PubMedPubMedCentralCrossRef
32.
Yang L, Liu L, Gao H, Pinnamaneni JP, Sanagasetti D, Singh VP, Wang K, Mathison M, Zhang Q, Chen F, et al. The stem cell factor SALL4 is an essential transcriptional regulator in mixed lineage leukemia-rearranged leukemogenesis. J Hematol Oncol. 2017;10(1):159–9.PubMedPubMedCentralCrossRef
33.
Liu Y-C, Kwon J, Fabiani E, Xiao Z, Liu YV, Follo MY, Liu J, Huang H, Gao C, Liu J. Demethylation and up-regulation of an oncogene after hypomethylating therapy. N Engl J Med. 2022;386(21):1998–2010.PubMedPubMedCentralCrossRef
34.
Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327(5971):1345–50.PubMedCrossRef
35.
Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. Thalidomide selectively inhibits tumor necrosis factor-alpha production by stimulated human monocytes. J Exp Med. 1991;173(3):699–703.PubMedCrossRef
36.
D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proceedings of the National Academy of Sciences 1994, 91(9):4082–4085.
37.
Matyskiela ME, Couto S, Zheng X, Lu G, Hui J, Stamp K, Drew C, Ren Y, Wang M, Carpenter A. SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate. Nat Chem Biol. 2018;14(10):981–7.PubMedCrossRef
38.
Komorowski J, Jerczyńska H, Siejka A, Barańska P, Ławnicka H, Pawłowska Z, Stępień H. Effect of thalidomide affecting VEGF secretion, cell migration, adhesion and capillary tube formation of human endothelial EA. hy 926 cells. Life Sci. 2006;78(22):2558–63.PubMedCrossRef
39.
Zheng W, Fu L. Effect of thalidomide combined with TP chemotherapy on serum VEGF and NRP-1 levels advanced esophageal cancer patients. Am J Translational Res. 2021;13(9):10809.
40.
Zhang X, Luo H. Effects of thalidomide on growth and VEGF-A expression in SW480 colon cancer cells. Oncol Lett. 2018;15(3):3313–20.PubMed
41.
Tong C, Liu H, Chen R, Zhu F. The effect of TACE in combination with thalidomide-mediated adjuvant therapy on the levels of VEGF and bFGF in patients with hepatocellular carcinoma. Am J Translational Res. 2021;13(5):5575.
42.
Fenton OS, Olafson KN, Pillai PS, Mitchell MJ, Langer R. Advances in biomaterials for drug delivery. Adv Mater. 2018;30(29):1705328.CrossRef
43.
Wang-Gillam A, Hubner RA, Siveke JT, Von Hoff DD, Belanger B, de Jong FA, Mirakhur B, Chen L-T. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: final overall survival analysis and characteristics of long-term survivors. Eur J Cancer. 2019;108:78–87.PubMedCrossRef
44.
Kim MS, Haney MJ, Zhao Y, Mahajan V, Deygen I, Klyachko NL, Inskoe E, Piroyan A, Sokolsky M, Okolie O. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomed Nanotechnol Biol Med. 2016;12(3):655–64.CrossRef
45.
Vader P, Mol EA, Pasterkamp G, Schiffelers RM. Extracellular vesicles for drug delivery. Adv Drug Deliv Rev. 2016;106:148–56.PubMedCrossRef
46.
Tran T-H, Mattheolabakis G, Aldawsari H, Amiji M. Exosomes as nanocarriers for immunotherapy of cancer and inflammatory diseases. Clin Immunol. 2015;160(1):46–58.PubMedCrossRef
47.
Liang G, Zhu Y, Ali DJ, Tian T, Xu H, Si K, Sun B, Chen B, Xiao Z. Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer. J Nanobiotechnol. 2020;18(1):1–15.CrossRef
48.
Shan S, Chen J, Sun Y, Wang Y, Xia B, Tan H, Pan C, Gu G, Zhong J, Qing G. Functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for diffuse intrinsic pontine gliomas therapy. Adv Sci 2022:2200353.
49.
Ma Y-S, Liu J-B, Lin L, Zhang H, Wu J-J, Shi Y, Jia C-Y, Zhang D-D, Yu F, Wang H-M. Exosomal microRNA-15a from mesenchymal stem cells impedes hepatocellular carcinoma progression via downregulation of SALL4. Cell death discovery. 2021;7(1):224.PubMedPubMedCentralCrossRef
50.
Yin C, Han Q, Xu D, Zheng B, Zhao X, Zhang J. SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC. Oncoimmunology. 2019;8(7):1601479–9.PubMedPubMedCentralCrossRef
Metadata
Title
SALL4 promotes angiogenesis in gastric cancer by regulating VEGF expression and targeting SALL4/VEGF pathway inhibits cancer progression
Authors
Fatma A. Abouelnazar
Xiaoxin Zhang
Jiahui Zhang
Maoye Wang
Dan Yu
Xueyan Zang
Jiayin Zhang
Yixin Li
Jing Xu
Qiurong Yang
Yue Zhou
Haozhou Tang
Yanzheng Wang
Jianmei Gu
Xu Zhang
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2023
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-023-02985-9

Other articles of this Issue 1/2023

Cancer Cell International 1/2023 Go to the issue

Research

Novel biomarker genes for the prediction of post-hepatectomy survival of patients with NAFLD-related hepatocellular carcinoma

Research

DSCC1 interacts with HSP90AB1 and promotes the progression of lung adenocarcinoma via regulating ER stress

Research

ncRNAs-mediated overexpression of STIL predict unfavorable prognosis and correlated with the efficacy of immunotherapy of hepatocellular carcinoma

Research

Krüppel-like factor 9 (KLF9) links hormone dysregulation and circadian disruption to breast cancer pathogenesis

Review

Tumor microenvironment in ovarian cancer peritoneal metastasis

Research

SQLE Knockdown inhibits bladder cancer progression by regulating the PTEN/AKT/GSK3β signaling pathway through P53
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits