Abstract
Purpose
Long noncoding RNAs (LncRNAs) play a pivotal role in gastric tumorigenesis, while exosomes facilitate the LncRNAs transferring to recipient cells. However, the roles of exosomal LncRNAs in gastric premalignant lesions (GPL) remain unclear.
Methods
We analyzed the expression of LncHOXA10 and its role in GPL progression. The protective effect of all-trans retinoic acid (ATRA) on GPL was explored in vitro and in vivo.
Results
Here, we found that LncHOXA10 expression was obviously increased in serum exosomes and gastric tissues from individuals with GPL, and exosomal LncHOXA10 from patients with GPL markedly promoted the malignant progression of human gastric epithelial cell line GES-1. Furthermore, RNA-pulldown assay revealed that LncHOXA10 mainly interacted with pyruvate carboxylase (PC), an essential enzyme in various cellular metabolic pathways. In gastric tissues from patients with GPL and gastric cancer (GC), PC was also upregulated and positively correlated with LncHOXA10 expression, which predicted a poor prognosis as well. Moreover, PC silencing attenuated the malignant effects of exosomal LncHOXA10 on GES-1 cells. ATRA also ameliorated the deterioration of GPL and prevented the malignant progression of GPL by reducing exosomal LncHOXA10 and PC expression.
Conclusions
Collectively, the LncHOXA10–PC axis participated in the early stage of GC tumorigenesis, and ATRA might be useful to prevent GPL from developing into GC because it targets this axis.
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Data availability statement
All data are available upon request.
Abbreviations
- GPL:
-
Gastric premalignant lesions
- PC:
-
Pyruvate carboxylase
- GC:
-
Gastric cancer
- ATRA:
-
All-trans retinoic acid
- LncRNAs:
-
Long noncoding RNAs
- LncHOXA10:
-
LncRNA Homeobox A10
- Oe control:
-
Overexpressing control
- Oe LncHOXA10:
-
Overexpressing LncHOXA10
- si-PC:
-
siRNA PC
References
Bouriez D et al (2018) Efficiency of all-trans retinoic acid on gastric cancer: a narrative literature review. Int J Mol Sci 19(11):3388
Cheng T et al (2011) Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc Natl Acad Sci USA 108(21):8674–8679
Christen S et al (2016) Breast cancer-derived lung metastases show increased pyruvate carboxylase-dependent anaplerosis. Cell Rep 17(3):837–848
Correa P (1988) A human model of gastric carcinogenesis. Cancer Res 48(13):3554–3560
Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 52(24):6735–6740
Cunningham TJ, Duester G (2015) Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nat Rev Mol Cell Biol 16(2):110–123
Dou Y et al (2020) All-trans retinoic acid enhances the effect of Fra-1 to inhibit cell proliferation and metabolism in cervical cancer. Biotechnol Lett 42(6):1051–1060
Du Y et al (2014) Chronic gastritis in China: a national multi-center survey. BMC Gastroenterol 14:21
Fan T et al (2020) Exosome-derived lncRNAs in lung cancer. Front Oncol 10:1728
Gao L et al (2021) All-trans retinoic acid suppressed GES-1 cell proliferation induced by exosomes from patients with precancerous lesions by arresting the cell cycle in S-phase. Eur J Cancer Prev 30(1):113–119
Guggenheim DE, Shah MA (2013) Gastric cancer epidemiology and risk factors. J Surg Oncol 107(3):230–236
Guo X et al (2020) Circulating exosomal gastric cancer-associated long noncoding RNA1 as a biomarker for early detection and monitoring progression of gastric cancer: a multiphase study. JAMA Surg 155(7):572–579
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674
Jin J et al (2015) Addition of all-trans-retinoic acid to omeprazole and sucralfate therapy improves the prognosis of gastric dysplasia. J Int Med Res 43(2):204–216
Kalluri R (2016) The biology and function of exosomes in cancer. J Clin Invest 126(4):1208–1215
Kang J et al (2013) Expression and clinical significance of pyruvate carboxylase in gastric adenocarcinoma. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 29(1):85–88
Li S et al (2020) Exosomal long noncoding RNA lnc-GNAQ-6:1 may serve as a diagnostic marker for gastric cancer. Clin Chim Acta 501:252–257
Lin JT (2014) Screening of gastric cancer: who, when, and how. Clin Gastroenterol Hepatol 12(1):135–138
Lin LY et al (2018) Tumor-originated exosomal lncUEGC1 as a circulating biomarker for early-stage gastric cancer. Mol Cancer 17(1):84
Lu Y et al (2020) Exosome-delivered LncHEIH promotes gastric cancer progression by upregulating EZH2 and stimulating methylation of the GSDME promoter. Front Cell Dev Biol 8:571297
Mao Y et al (2017) Transcriptome analysis of miRNA-lncRNA-mRNA interactions in the malignant transformation process of gastric cancer initiation. Cancer Gene Ther 24(6):267–275
Mao Q et al (2019) LncRNA KLF3-AS1 in human mesenchymal stem cell-derived exosomes ameliorates pyroptosis of cardiomyocytes and myocardial infarction through miR-138-5p/Sirt1 axis. Stem Cell Res Ther 10(1):393
Matsumoto M et al (2005) Retinoic acid formation from retinol in the human gastric mucosa: role of class IV alcohol dehydrogenase and its relevance to morphological changes. Am J Physiol Gastrointest Liver Physiol 289(3):G429-433
Meng Q et al (2020) Long noncoding RNA MIR99AHG promotes gastric cancer progression by inducing EMT and inhibiting apoptosis via miR577/FOXP1 axis. Cancer Cell Int 20:414
Nguyen PH et al (2016) All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth. Oncogene 35(43):5619–5628
Ni X et al (2019) The success and the challenge of all-trans retinoic acid in the treatment of cancer. Crit Rev Food Sci Nutr 59(sup1):S71–S80
Ni C et al (2020) Breast cancer-derived exosomes transmit lncRNA SNHG16 to induce CD73+gammadelta1 Treg cells. Signal Transduct Target Ther 5(1):41
Piao HY et al (2021) Exosome-transmitted lncRNA PCGEM1 promotes invasive and metastasis in gastric cancer by maintaining the stability of SNAI1. Clin Transl Oncol 23(2):246–256
Pinweha P et al (2019) MicroRNA-143–3p targets pyruvate carboxylase expression and controls proliferation and migration of MDA-MB-231cells. Arch Biochem Biophys 677:108169
Quinn JJ, Chang HY (2016) Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17(1):47–62
Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200(4):373–383
Ratajczak J et al (2006) Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20(9):1487–1495
Rawla P, Barsouk A (2019) Epidemiology of gastric cancer: global trends, risk factors and prevention. Prz Gastroenterol 14(1):26–38
Sandoval-Borquez A et al (2015) Noncoding genomics in gastric cancer and the gastric precancerous cascade: pathogenesis and biomarkers. Dis Markers 2015:503762
Sellers K et al (2015) Pyruvate carboxylase is critical for non-small-cell lung cancer proliferation. J Clin Invest 125(2):687–698
Song H et al (2015) Incidence of gastric cancer among patients with gastric precancerous lesions: observational cohort study in a low risk Western population. BMJ 351:h3867
Sun W et al (2016) Roles of long noncoding RNAs in gastric cancer and their clinical applications. J Cancer Res Clin Oncol 142(11):2231–2237
Sun Z et al (2018) Emerging role of exosome-derived long non-coding RNAs in tumor microenvironment. Mol Cancer 17(1):82
Terao M et al (2019) Role of mitochondria and cardiolipins in growth inhibition of breast cancer cells by retinoic acid. J Exp Clin Cancer Res 38(1):436
Wang CJ et al (2019a) The lncRNA UCA1 promotes proliferation, migration, immune escape and inhibits apoptosis in gastric cancer by sponging anti-tumor miRNAs. Mol Cancer 18(1):115
Wang J et al (2019b) Exosome-mediated transfer of lncRNA HOTTIP promotes cisplatin resistance in gastric cancer cells by regulating HMGA1/miR-218 axis. Onco Targets Ther 12:11325–11338
Wang L et al (2020a) Exosome-transferred LINC01559 promotes the progression of gastric cancer via PI3K/AKT signaling pathway. Cell Death Dis 11(9):723
Wang C et al (2020b) All-trans retinoic acid rescues the tumor suppressive role of RAR-beta by Inhibiting LncHOXA10 expression in gastric tumorigenesis. Nutr Cancer. https://doi.org/10.1080/01635581.2020.1823006
Xia Q et al (2017) Proteomic analysis of cell cycle arrest and differentiation induction caused by ATPR, a derivative of all-trans retinoic acid, in human gastric cancer SGC-7901 cells. Proteomics Clin Appl 11(7–8):1600099
You WC (1991) Gastric mucosal lesions and their transition rates in high risk population of gastric cancer. Zhonghua Zhong Liu Za Zhi 13(2):100–102
You WC et al (1993) Precancerous gastric lesions in a population at high risk of stomach cancer. Cancer Res 53(6):1317–1321
Yu W et al (2021) Exosome-based liquid biopsies in cancer: opportunities and challenges. Ann Oncol 32(4):466–477
Zhang C et al (2018) Exosome: function and role in cancer metastasis and drug resistance. Technol Cancer Res Treat 17:1533033818763450
Zhang T et al (2020) microRNA-365 inhibits YAP through TLR4-mediated IRF3 phosphorylation and thereby alleviates gastric precancerous lesions. Cancer Cell Int 20(1):549
Funding
This study was supported by Grants from the National Nature Science Research Grant of China (81502806, 81973049), the University Natural Science Research Project of Anhui Province (No. KJ2019A0227) and Anhui Provincial Natural Science Foundation (No. 1808085MH258).
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ALH and QHZ conceived and designed the study and helped polish the manuscript. CW carried out the experiments, analyzed the data and drafted the manuscript. DDZ, XS, KXW, TTW, and XL conducted a part of the experiments. DMZ and WSY analyzed the experimental data. TX, SQQ, and MT helped in the sampling of biological specimen. All authors read and approved the final manuscript.
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Wang, C., Zhao, D., Shu, X. et al. Protective effects of all-trans retinoic acid against gastric premalignant lesions by repressing exosomal LncHOXA10–pyruvate carboxylase axis. J Cancer Res Clin Oncol 148, 121–135 (2022). https://doi.org/10.1007/s00432-021-03820-2
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DOI: https://doi.org/10.1007/s00432-021-03820-2