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LITAF inhibits colorectal cancer stemness and metastatic behavior by regulating FOXO1-mediated SIRT1 expression

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Abstract

Lipopolysaccharide-induced tumor necrosis factor alpha factor (LITAF) is a transcription factor that activates the transcription of TNF-α and regulates the inflammatory response. LITAF has been found to have potential anti-cancer effects of in several tumors. However, the role of LITAF in colorectal cancer (CRC) remains unclear. Through a comprehensive pan-cancer analysis of the Cancer Genome Atlas (TCGA), LITAF was identified as a differentially downregulated gene in CRC. We hypothesized that LITAF may participate in the modulation of CRC progression. The present study was aimed to investigate the expression profile of LITAF in CRC and its effect on metastatic behavior and stemness as well as the underlying molecular mechanism. The expression profile of LITAF in CRC, and its relationship with the prognosis of CRC were explored using public databases. LITAF expression was detected by quantitative real-time PCR (qRT-PCR), western blot, and immunohistochemistry. Furthermore, the effects of overexpression or knockdown of LITAF on cell proliferation, apoptosis, migration, invasion, and stemness of CRC cells were investigated in vitro. The regulatory effect of LITAF on forkhead Box O 1 (FOXO1)-sirtuin 1 (SIRT1) signaling axis was also explored. In addition, a xenograft mouse model was used to investigate the in-vivo role of LITAF. LITAF was downregulated in tumor tissues and its expression was associated with the prognosis, pathological stage and liver metastasis. In-vitro experiments confirmed that LITAF inhibited tumor cell proliferation, migration, invasion and stemness, and induced cell apoptosis. In vivo experiments demonstrated that LITAF inhibited the tumorigenicity and liver metastasis in tumor-bearing mice. Additionally, LITAF promoted FOXO1-mediated SIRT1 inhibition, thus regulating cancer stemness and malignant phenotypes. LITAF was silenced in CRC and it participated in the progression of CRC by inhibiting CRC cell stemness, and malignant phenotypes. Therefore, LITAF may serve as a novel biomarker of CRC prognosis.

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References

  1. Dekker E et al (2019) Colorectal cancer. Lancet 394(10207):1467–1480

    Article  PubMed  Google Scholar 

  2. Dariya B et al (2020) Colorectal cancer biology, diagnosis, and therapeutic approaches. Crit Rev Oncog 25(2):71–94

    Article  PubMed  Google Scholar 

  3. Wang J et al (2020) Cinobufacini inhibits colon cancer invasion and metastasis via suppressing Wnt/beta-catenin signaling pathway and EMT. Am J Chin Med 48(3):703–718

    Article  CAS  PubMed  Google Scholar 

  4. Fiorentino F et al (2022) Sirtuin modulators: past, present, and future perspectives. Future Med Chem 14(12):915–939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Imai S, Guarente L (2014) NAD+ and sirtuins in aging and disease. Trends Cell Biol 24(8):464–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Garcia-Peterson LM, Li X (2021) Trending topics of SIRT1 in tumorigenicity. Biochim Biophys Acta Gen Subj 1865(9):129952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zu G et al (2016) Clinicopathological significance of SIRT1 expression in colorectal cancer: a systematic review and meta analysis. Int J Surg 26:32–37

    Article  PubMed  Google Scholar 

  8. Sun LN et al (2017) SIRT1 suppresses colorectal cancer metastasis by transcriptional repression of miR-15b-5p. Cancer Lett 409:104–115

    Article  CAS  PubMed  Google Scholar 

  9. Fang H et al (2022) SIRT1 induces the accumulation of TAMs at colorectal cancer tumor sites via the CXCR4/CXCL12 axis. Cell Immunol 371:104458

    Article  CAS  PubMed  Google Scholar 

  10. An Y et al (2020) SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop. Cell Death Dis 11(2):115

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wang TW et al (2020) SIRT1-mediated expression of CD24 and epigenetic suppression of novel tumor suppressor miR-1185-1 increases colorectal cancer stemness. Cancer Res 80(23):5257–5269

    Article  CAS  PubMed  Google Scholar 

  12. Yao J et al (2021) FBXW11 contributes to stem-cell-like features and liver metastasis through regulating HIC1-mediated SIRT1 transcription in colorectal cancer. Cell Death Dis 12(10):930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang S et al (2021) Role of forkhead box O proteins in hepatocellular carcinoma biology and progression (review). Front Oncol 11:667730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu Y et al (2022) The FOXO family of transcription factors: key molecular players in gastric cancer. J Mol Med 100(7):997–1015

    Article  CAS  PubMed  Google Scholar 

  15. Chen F et al (2021) Circular RNA ubiquitin-associated protein 2 enhances autophagy and promotes colorectal cancer progression and metastasis via miR-582-5p/FOXO1 signaling. J Genet Genomics 48(12):1091–1103

    Article  CAS  PubMed  Google Scholar 

  16. Dai X, Xie Y, Dong M (2022) Cancer-associated fibroblasts derived extracellular vesicles promote angiogenesis of colorectal adenocarcinoma cells through miR-135b-5p/FOXO1 axis. Cancer Biol Ther 23(1):76–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim SY et al (2016) Forkhead transcription factor FOXO1 inhibits angiogenesis in gastric cancer in relation to SIRT1. Cancer Res Treat 48(1):345–354

    Article  CAS  PubMed  Google Scholar 

  18. Liu H et al (2019) Oncogenic USP22 supports gastric cancer growth and metastasis by activating c-Myc/NAMPT/SIRT1-dependent FOXO1 and YAP signaling. Aging 11(21):9643–9660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fukui M et al (2021) Mechanism underlying resveratrol’s attenuation of paclitaxel cytotoxicity in human breast cancer cells: role of the SIRT1-FOXO1-HER3 signaling pathway. Cancer Treat Res Commun 28:100386

    Article  PubMed  Google Scholar 

  20. Liu H et al (2015) UDP-glucuronosyltransferase 1A determinates intracellular accumulation and anti-cancer effect of beta-lapachone in human colon cancer cells. PLoS ONE 10(2):e0117051

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ko YS, Kim NY, Pyo JS (2020) Clinicopathological significance and angiogenic role of the constitutive phosphorylation of the FOXO1 transcription factor in colorectal cancer. Pathol Res Pract 216(11):153150

    Article  CAS  PubMed  Google Scholar 

  22. Zou J et al (2015) Lipopolysaccharide-induced tumor necrosis factor-alpha factor enhances inflammation and is associated with cancer (review). Mol Med Rep 12(5):6399–6404

    Article  CAS  PubMed  Google Scholar 

  23. Zhou Y et al (2018) LITAF is a potential tumor suppressor in pancreatic cancer. Oncotarget 9(3):3131–3142

    Article  PubMed  Google Scholar 

  24. Hoey C et al (2018) miRNA-106a and prostate cancer radioresistance: a novel role for LITAF in ATM regulation. Mol Oncol 12(8):1324–1341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Huang C et al (2019) LITAF enhances radiosensitivity of human glioma cells via the FoxO1 pathway. Cell Mol Neurobiol 39(6):871–882

    Article  CAS  PubMed  Google Scholar 

  26. Yu Z et al (2022) Increased expression of INHBA is correlated with poor prognosis and high immune infiltrating level in breast cancer. Front Bioinform 2:729902

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen X et al (2023) Prognostic biomarker SLCO4A1 is correlated with tumor immune infiltration in colon adenocarcinoma. Mediat Inflamm 2023:4926474

    Article  Google Scholar 

  28. Jian L et al (2023) GLUT10 is a novel immune regulator involved in lung cancer immune cell infiltration and predicts worse survival when transcriptionally downregulated. Heliyon 9(3):e13836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. World Medical, A (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310(20):2191–2194

    Article  Google Scholar 

  30. in Guide for the Care and Use of Laboratory Animals, th, Editor. (2011) Washington

  31. Chang TY et al (2022) ANGPTL1 attenuates cancer migration, invasion, and stemness through regulating FOXO3a-mediated SOX2 expression in colorectal cancer. Clin Sci 136(9):657–673

    Article  CAS  Google Scholar 

  32. Chandra R et al (2021) The colorectal cancer tumor microenvironment and its impact on liver and lung metastasis. Cancers 13(24):6206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zheng X et al (2021) Communication between epithelial-mesenchymal plasticity and cancer stem cells: new insights into cancer progression. Front Oncol 11:617597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Matsumura Y et al (2004) PIG7/LITAF gene mutation and overexpression of its gene product in extramammary Paget’s disease. Int J Cancer 111(2):218–223

    Article  CAS  PubMed  Google Scholar 

  35. Chen YC et al (2020) Involvement of the MicroRNA-1-LITAF axis in gastric cancer cell growth and invasion. Anticancer Res 40(11):6247–6256

    Article  CAS  PubMed  Google Scholar 

  36. Pastushenko I, Blanpain C (2019) EMT transition states during tumor progression and metastasis. Trends Cell Biol 29(3):212–226

    Article  CAS  PubMed  Google Scholar 

  37. Zhang N et al (2021) Novel therapeutic strategies: targeting epithelial-mesenchymal transition in colorectal cancer. Lancet Oncol 22(8):e358–e368

    Article  CAS  PubMed  Google Scholar 

  38. Wong SHM et al (2018) E-cadherin: its dysregulation in carcinogenesis and clinical implications. Crit Rev Oncol Hematol 121:11–22

    Article  PubMed  Google Scholar 

  39. Luo Y et al (2018) Upregulated N-cadherin expression is associated with poor prognosis in epithelial-derived solid tumours: a meta-analysis. Eur J Clin Invest 48(4):e12903

    Article  PubMed  PubMed Central  Google Scholar 

  40. Chi Z et al (2021) LINC00473 downregulation facilitates trophoblast cell migration and invasion via the miR-15a-5p/LITAF axis in pre-eclampsia. Environ Toxicol 36(8):1618–1627

    Article  CAS  PubMed  Google Scholar 

  41. Celia-Terrassa T, Jolly MK (2020) Cancer stem cells and epithelial-to-mesenchymal transition in cancer metastasis. Cold Spring Harb Perspect Med 10(7):036905

    Article  Google Scholar 

  42. You L, Guo X, Huang Y (2018) Correlation of cancer stem-cell markers OCT4, SOX2, and NANOG with clinicopathological features and prognosis in operative patients with rectal cancer. Yonsei Med J 59(1):35–42

    Article  CAS  PubMed  Google Scholar 

  43. Li Y et al (2019) Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9. Signal Transduct Target Ther 4:48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lin X et al (2019) HBX-induced miR-5188 impairs FOXO1 to stimulate beta-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma. Theranostics 9(25):7583–7598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zou Y et al (2020) Timeless-stimulated miR-5188-FOXO1/beta-catenin-c-Jun feedback loop promotes stemness via ubiquitination of beta-catenin in breast cancer. Mol Ther 28(1):313–327

    Article  CAS  PubMed  Google Scholar 

  46. Jiang Y et al (2020) Resveratrol promotes osteogenesis via activating SIRT1/FoxO1 pathway in osteoporosis mice. Life Sci 246:117422

    Article  CAS  PubMed  Google Scholar 

  47. Jing Z et al (2021) Phosphocreatine promotes osteoblastic activities in H2O2-induced MC3T3-E1 cells by regulating SIRT1/FOXO1/PGC-1alpha signaling pathway. Curr Pharm Biotechnol 22(5):609–621

    Article  CAS  PubMed  Google Scholar 

  48. Chen X et al (2022) Asiatic acid improves high-fat-diet-induced osteoporosis in mice via regulating SIRT1/FOXO1 signaling and inhibiting oxidative stress. Histol Histopathol 37(8):769–777

    CAS  PubMed  Google Scholar 

  49. Ren BC et al (2020) Curcumin alleviates oxidative stress and inhibits apoptosis in diabetic cardiomyopathy via Sirt1-Foxo1 and PI3K-Akt signalling pathways. J Cell Mol Med 24(21):12355–12367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mao ZJ, Xia WS, Chai F (2021) Yunpi Heluo decoction attenuates insulin resistance by regulating SIRT1-FoxO1 autophagy pathway in skeletal muscle of Zucker diabetic fatty rats. J Ethnopharmacol 270:113828

    Article  CAS  PubMed  Google Scholar 

  51. Mao Z et al (2022) Yunpi Heluo decoction reduces ectopic deposition of lipids by regulating the SIRT1-FoxO1 autophagy pathway in diabetic rats. Pharm Biol 60(1):579–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tan Y et al (2022) Lingbao huxin pill alleviates apoptosis and inflammation at infarct border zone through SIRT1-mediated FOXO1 and NF- kappa B pathways in rat model of acute myocardial infarction. Chin J Integr Med 28(4):330–338

    Article  CAS  PubMed  Google Scholar 

  53. Yang X, Wu K (2022) Artemisinin alleviates cerebral ischemia/reperfusion injury via regulation of the forkhead transcription factor O1 signaling pathway. Evid Based Complement Alternat Med 2022:7824436

    PubMed  PubMed Central  Google Scholar 

  54. Zhang D et al (2022) LncRNA SNHG8 sponges miR-449c-5p and regulates the SIRT1/FoxO1 pathway to affect microglia activation and blood-brain barrier permeability in ischemic stroke. J Leukoc Biol 111(5):953–966

    Article  CAS  PubMed  Google Scholar 

  55. Wang Y et al (2018) Roles of SIRT1/FoxO1/SREBP-1 in the development of progestin resistance in endometrial cancer. Arch Gynecol Obstet 298(5):961–969

    Article  CAS  PubMed  Google Scholar 

  56. Liu CL et al (2022) Inhibition of glioblastoma progression by Urolithin A in vitro and in vivo by regulating Sirt1-FOXO1 axis via ERK/AKT signaling pathways. Neoplasma 69(1):80–94

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81974379), the Natural Science Foundation of Shanghai (Grant No. 19ZR1438700) and the Interdisciplinary Program of Shanghai Jiao Tong University (Grant No. ZH2018QNB05).

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  1. Jiao Guan and Zheng-Yun Zhang have contributed equally to the work.

Authors and Affiliations

  1. Department of Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    Jiao Guan & Lei Qin

  2. Department of Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China

    Jiao Guan, Zheng-Yun Zhang, Xin-Ping Wang & Zun-Qiang Zhou

  3. Department of Emergency, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China

    Jian-Hua Sun

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  1. Jiao Guan
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Contributions

Conceptualization, Methodology, and Writing—Original Draft were performed by JG; Formal analysis, Resources, and Investigation were performed by Z-YZ; Formal analysis, Visualization and Data Curation were performed by J-HS; Project administration, Supervision, and Validation were performed by X-PW; Validation, Supervision, and Writing—Review & Editing were performed by Z-QZ and LQ. All authors read and approved the final manuscript.

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Correspondence to Zun-Qiang Zhou or Lei Qin.

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All procedures were approved by the human Ethics Committee of the First Affiliated Hospital of Soochow University. The animal experiment was supported by the Animal Ethics Committee of the First Affiliated Hospital of Soochow University.

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Guan, J., Zhang, ZY., Sun, JH. et al. LITAF inhibits colorectal cancer stemness and metastatic behavior by regulating FOXO1-mediated SIRT1 expression. Clin Exp Metastasis 40, 309–320 (2023). https://doi.org/10.1007/s10585-023-10213-x

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