BATF3 promotes malignant phenotype of colorectal cancer through the S1PR1/p-STAT3/miR-155-3p/WDR82 axis



Encouraging insight into novel underlying mechanisms targeting abnormal biological pathways in colorectal cancer (CRC) are currently under investigation, edging closer and closer to clinical use. Of note, basic leucine zipper ATF-like transcription factor 3 (BATF3) has been implicated with the tumorigenicity of CRC. The current study aimed to elucidate the oncogenic BATF3-mediated S1PR1/p-STAT3/miR-155-3p/WDR82 axis in CRC. Initially, clinical samples of CRC tissues as well as CRC cell lines were collected to evaluate the expression patterns of BATF3/S1PR1/p-STAT3/miR-155-3p/WDR82. Dual luciferase assay was employed to assess the binding affinity between miR-155-3p and WDR82. Artificial modulation of BATF3 (down- and overexpression) was conducted to measure the malignant phenotypes of CRC cells, while tumor-bearing mice were examined to determine the in vivo effects. BATF3 facilitated the proliferative, migratory, and invasive potential of CRC cells by upregulating S1PR1. Besides, the stimulatory effect of S1PR1 was realized via restored p-STAT3 expression. Furthermore, p-STAT3 was evidenced to heighten the expression of miR-155-3p and subsequently restrict the expression of its target gene WDR82. The in vivo assays provided data further substantiating the in vitro findings that inactivation of the BATF3/S1PR1/p-STAT3/miR-155-3p/WDR82 axis suppresses CRC tumor growth. Collectively, the results of the present study emphasize the oncogenic function of BATF3 illustrated by the reinforcement the biological processes of proliferation, invasion, as well as the metastatic capacity of CRC cells through activating the S1PR1/p-STAT3/miR-155-3p/WDR82 axis.

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Fig. 1: The pathogenesis of CRC is enhanced by BATF3 through S1PR1 elevation.
Fig. 2: The pathogenesis of CRC is enhanced by S1PR1 through p-STAT3 elevation.
Fig. 3: CRC progression was promoted by p-STAT3 through WDR82 repression via elevating miR-155-3p.
Fig. 4: BATF3/S1PR1/p-STAT3/miR-155-3p/WDR82 axis inhibition plays an inhibiting role in CRC development.
Fig. 5: BATF3/S1PR1/p-STAT3/miR-155-3p/WDR82 axis inhibition suppresses the growth of CRC tumors in vivo.
Fig. 6: The mechanism graph of the regulatory network and function of BATF3.


  1. 1.

    Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394:1467–80.

    Article  PubMed  Google Scholar 

  2. 2.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  3. 3.

    Kuipers EJ, Grady WM, Lieberman D, Seufferlein T, Sung JJ, Boelens PG, et al. Colorectal cancer. Nat Rev Dis Prim. 2015;1:15065.

    Article  PubMed  Google Scholar 

  4. 4.

    Nassar D, Blanpain C. Cancer stem cells: basic concepts and therapeutic implications. Annu Rev Pathol. 2016;11:47–76.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med. 2009;361:2449–60.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Duran-Sanchon S, Moreno L, Auge JM, Serra-Burriel M, Cuatrecasas M, Moreira L, et al. Identification and validation of microRNA profiles in fecal samples for detection of colorectal cancer. Gastroenterology. 2019;

  7. 7.

    Lech G, Slotwinski R, Slodkowski M, Krasnodebski IW. Colorectal cancer tumour markers and biomarkers: recent therapeutic advances. World J Gastroenterol. 2016;22:1745–55.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Cao L, Liu Y, Wang D, Huang L, Li F, Liu J, et al. MiR-760 suppresses human colorectal cancer growth by targeting BATF3/AP-1/cyclinD1 signaling. J Exp Clin Cancer Res. 2018;37:83.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Vrzalikova K, Ibrahim M, Vockerodt M, Perry T, Margielewska S, Lupino L, et al. S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells. Leukemia. 2018;32:214–23.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Liu Y, Zhi Y, Song H, Zong M, Yi J, Mao G, et al. S1PR1 promotes proliferation and inhibits apoptosis of esophageal squamous cell carcinoma through activating STAT3 pathway. J Exp Clin Cancer Res. 2019;38:369.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Wei H, Li Y, Ning Q, Suo ZM. Regulation of miR-155 affects the invasion and migration of gastric carcinoma cells by modulating the STAT3 signaling pathway. Oncol Lett. 2018;16:4137–42.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science. 2001;294:853–8.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Liu H, Li Y, Li J, Liu Y, Cui B. H3K4me3 and Wdr82 are associated with tumor progression and a favorable prognosis in human colorectal cancer. Oncol Lett. 2018;16:2125–34.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ji K, Zhang M, Chu Q, Gan Y, Ren H, Zhang L, et al. The role of p-STAT3 as a prognostic and clinicopathological marker in colorectal cancer: a systematic review and meta-analysis. PLoS ONE. 2016;11:e0160125.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Wang SW, Sun YM. The IL-6/JAK/STAT3 pathway: potential therapeutic strategies in treating colorectal cancer (Review). Int J Oncol. 2014;44:1032–40.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Kitamura H, Ohno Y, Toyoshima Y, Ohtake J, Homma S, Kawamura H, et al. Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy. Cancer Sci. 2017;108:1947–52.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Xue H, Yuan G, Guo X, Liu Q, Zhang J, Gao X, et al. A novel tumor-promoting mechanism of IL6 and the therapeutic efficacy of tocilizumab: Hypoxia-induced IL6 is a potent autophagy initiator in glioblastoma via the p-STAT3-MIR155-3p-CREBRF pathway. Autophagy. 2016;12:1129–52.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Daniel SK, Seo YD, Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies. Semin Cancer Biol. 2019;

  19. 19.

    Huang Y, Sun H, Ma X, Zeng Y, Pan Y, Yu D, et al. HLA-F-AS1/miR-330-3p/PFN1 axis promotes colorectal cancer progression. Life Sci. 2019;

  20. 20.

    Crockett SD, Nagtegaal ID. Terminology, molecular features, epidemiology, and management of serrated colorectal neoplasia. Gastroenterology. 2019;157:949–66 e4.

    Article  PubMed  Google Scholar 

  21. 21.

    Jevsinek Skok D, Hauptman N, Bostjancic E, Zidar N. The integrative knowledge base for miRNA-mRNA expression in colorectal cancer. Sci Rep. 2019;9:18065.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Theisen DJ, Ferris ST, Briseno CG, Kretzer N, Iwata A, Murphy KM, et al. Batf3-dependent genes control tumor rejection induced by dendritic cells independently of cross-presentation. Cancer Immunol Res. 2019;7:29–39.

    CAS  PubMed  Google Scholar 

  23. 23.

    Yang M, Li G, Fan L, Zhang G, Xu J, Zhang J. Circular RNA circ_0034642 elevates BATF3 expression and promotes cell proliferation and invasion through miR-1205 in glioma. Biochem Biophys Res Commun. 2019;508:980–5.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Pang F, Chen Z, Wang C, Zhang M, Zhang Z, Yang X, et al. Comprehensive analysis of differentially expressed microRNAs and mRNAs in MDBK cells expressing bovine papillomavirus E5 oncogene. PeerJ. 2019;7:e8098.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Lin Q, Ren L, Jian M, Xu P, Li J, Zheng P, et al. The mechanism of the premetastatic niche facilitating colorectal cancer liver metastasis generated from myeloid-derived suppressor cells induced by the S1PR1-STAT3 signaling pathway. Cell Death Dis. 2019;10:693.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Sang Y, Chen B, Song X, Li Y, Liang Y, Han D, et al. circRNA_0025202 regulates tamoxifen sensitivity and tumor progression via regulating the miR-182-5p/FOXO3a axis in breast cancer. Mol Ther. 2019;27:1638–52.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Wang A, Deng S, Chen X, Yu C, Du Q, Wu Y, et al. miR-29a-5p/STAT3 positive feedback loop regulates TETs in colitis-associated colorectal cancer. Inflamm Bowel Dis. 2019;

  28. 28.

    Khan MI, Hamid A, Adhami VM, Lall RK, Mukhtar H. Role of epithelial mesenchymal transition in prostate tumorigenesis. Curr Pharm Des. 2015;21:1240–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Lamouille S, Subramanyam D, Blelloch R, Derynck R. Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. Curr Opin Cell Biol. 2013;25:200–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Serrels B, McGivern N, Canel M, Byron A, Johnson SC, McSorley HJ, et al. IL-33 and ST2 mediate FAK-dependent antitumor immune evasion through transcriptional networks. Sci Signal. 2017;10:eaan8355.

    Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Changyong Zhao or Saimin Dai.

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Li, P., Weng, Z., Li, P. et al. BATF3 promotes malignant phenotype of colorectal cancer through the S1PR1/p-STAT3/miR-155-3p/WDR82 axis. Cancer Gene Ther (2020).

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