LMX1A inhibits C-Myc expression through ANGPTL4 to exert tumor suppressive role in gastric cancer
Autoři:
Peiyu Qian aff001; Jian Li aff002; Xiaohong Zhang aff002; Fan Li aff002; Songhua Bei aff002; Huanqing Li aff002; Qi Sun aff002; Li Feng aff002
Působiště autorů:
Minhang Fudan Medical Research Cooperative Development Research Institute, Minhang Hospital, Fudan University, Shanghai, Minhang District, Shanghai, P.R. China
aff001; Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, Minhang District, Shanghai, P.R. China
aff002
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0221640
Souhrn
Our research group has showed that the LIM homeobox transcription factor 1 alpha (LMX1A) is inactivated in gastric cancers. Overexpression of LMX1A inhibits tumor growth. However, the mechanisms remains unclear. Considering LMX1A as a transcription factor, a comparison of RNA-seq between gastric cancer cells (GCCs) and GCCs with LMX1A overexpressed was performed to identify genes transcriptionally activated by LMX1A. Among the potential LMX1A target genes, angiopoietin-like 4 (ANGPTL4) has been reported to be an important tumor suppressor and thus was selected for further validation and research. Both LMX1A and ANGPTL4 showed downregulated expression in gastric cancer samples. More importantly, the expression of LMX1A is positively correlated with ANGPTL4, without including other family members in gastric cancer cell lines. What’s more, knockdown of ANGPTL4 rescued the tumor suppressive phenotype of LMX1A overexpression, which indicated that LMX1A upregulates ANGPTL4 to exert its role. Mechanistically, we found that LMX1A inhibited the expression of the oncogene C-Myc, which is alleviated by ANGPTL4 knockdown. In general, our results showed that LMX1A exerts its tumor suppressive role by activating ANGPTL4 to inhibit C-Myc.
Klíčová slova:
Gastric cancer – Gene regulation – Hyperexpression techniques – RNA extraction – RNA sequencing – Transcription factors – Tumor suppressor genes – Suppressor genes
Zdroje
1. Hobert O, Westphal H. Functions of LIM-homeobox genes. Trends in genetics: TIG. 2000;16(2):75–83. doi: 10.1016/s0168-9525(99)01883-1 10652534.
2. Cai J, Donaldson A, Yang M, German MS, Enikolopov G, Iacovitti L. The role of Lmx1a in the differentiation of human embryonic stem cells into midbrain dopamine neurons in culture and after transplantation into a Parkinson’s disease model. Stem cells. 2009;27(1):220–9. doi: 10.1634/stemcells.2008-0734 18832589.
3. Chizhikov VV, Lindgren AG, Mishima Y, Roberts RW, Aldinger KA, Miesegaes GR, et al. Lmx1a regulates fates and location of cells originating from the cerebellar rhombic lip and telencephalic cortical hem. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(23):10725–30. doi: 10.1073/pnas.0910786107 20498066
4. Dong W, Feng L, Xie Y, Zhang H, Wu Y. Hypermethylation-mediated reduction of LMX1A expression in gastric cancer. Cancer science. 2011;102(2):361–6. doi: 10.1111/j.1349-7006.2010.01804.x 21159062.
5. Su HY, Lai HC, Lin YW, Chou YC, Liu CY, Yu MH. An epigenetic marker panel for screening and prognostic prediction of ovarian cancer. International journal of cancer. 2009;124(2):387–93. doi: 10.1002/ijc.23957 18942711.
6. Lai HC, Lin YW, Huang TH, Yan P, Huang RL, Wang HC, et al. Identification of novel DNA methylation markers in cervical cancer. International journal of cancer. 2008;123(1):161–7. doi: 10.1002/ijc.23519 18398837.
7. Chao TK, Yo YT, Liao YP, Wang YC, Su PH, Huang TS, et al. LIM-homeobox transcription factor 1, alpha (LMX1A) inhibits tumourigenesis, epithelial-mesenchymal transition and stem-like properties of epithelial ovarian cancer. Gynecologic oncology. 2013;128(3):475–82. doi: 10.1016/j.ygyno.2012.12.018 23270808.
8. Zhang X, Lu W, Zheng Y, Wang W, Bai L, Chen L, et al. In situ analysis of intrahepatic virological events in chronic hepatitis B virus infection. Journal of Clinical Investigation. 2016;126(3):1079. doi: 10.1172/JCI83339 26901811
9. German MS, Wang J, Fernald AA, Espinosa R 3rd, Le Beau MM, Bell GI. Localization of the genes encoding two transcription factors, LMX1 and CDX3, regulating insulin gene expression to human chromosomes 1 and 13. Genomics. 1994;24(2):403–4. doi: 10.1006/geno.1994.1639 7698771.
10. Feng L, Xie Y, Zhao Z, Lian WJCB. LMX1A inhibits metastasis of gastric cancer cells through negative regulation of β-catenin. Toxicology 2016;32(2):133–9.
11. Minter-Dykhouse K, Ward I, Huen MS, Chen J, Lou Z. Distinct versus overlapping functions of MDC1 and 53BP1 in DNA damage response and tumorigenesis. The Journal of cell biology. 2008;181(5):727–35. doi: 10.1083/jcb.200801083 18504301
12. Okochi-Takada E, Hattori N, Tsukamoto T, Miyamoto K, Ando T, Ito S, et al. ANGPTL4 is a secreted tumor suppressor that inhibits angiogenesis. Oncogene. 2014;33(17):2273–8. doi: 10.1038/onc.2013.174 23686315.
13. Xu AG, Li SG, Liu JH, Gan AH. Function of apoptosis and expression of the proteins Bcl-2, p53 and C-myc in the development of gastric cancer. World Journal of Gastroenterology. 2001;7(3):403. doi: 10.3748/wjg.v7.i3.403 11819799
14. Tan P, Yeoh KG. Genetics and Molecular Pathogenesis of Gastric Adenocarcinoma. Gastroenterology. 2015;149(5):1153–62.e3. doi: 10.1053/j.gastro.2015.05.059 26073375
Článek vyšel v časopise
PLOS One
2019 Číslo 9
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Je libo čepici místo mozkového implantátu?
- Pomůže v budoucnu s triáží na pohotovostech umělá inteligence?
- AI může chirurgům poskytnout cenná data i zpětnou vazbu v reálném čase
- Nová metoda odlišení nádorové tkáně může zpřesnit resekci glioblastomů
Nejčtenější v tomto čísle
- Graviola (Annona muricata) attenuates behavioural alterations and testicular oxidative stress induced by streptozotocin in diabetic rats
- CH(II), a cerebroprotein hydrolysate, exhibits potential neuro-protective effect on Alzheimer’s disease
- Comparison between Aptima Assays (Hologic) and the Allplex STI Essential Assay (Seegene) for the diagnosis of Sexually transmitted infections
- Assessment of glucose-6-phosphate dehydrogenase activity using CareStart G6PD rapid diagnostic test and associated genetic variants in Plasmodium vivax malaria endemic setting in Mauritania
Zvyšte si kvalifikaci online z pohodlí domova
Všechny kurzy