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Fascin protein stabilization by miR-146a implicated in the process of a chronic inflammation-related colon carcinogenesis model

  • Original Research Paper
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Abstract

Objective

In sporadic colon tumors, multistep process of well-known genetic alterations accelerates carcinogenesis; however, this does not appear to be the case in inflammation-related ones. We previously established a model of inflammation-related colon carcinogenesis using human colonic adenoma cells, and identified fascin as a driver gene of this process. We analyzed the microRNAs involved in the stable fascin expression in colon adenocarcinoma cells.

Materials and methods

miRNA microarray analysis was performed using FPCK-1-1 adenoma cells and its-derived FPCKpP1-4 adenocarcinoma cells through chronic inflammation. To assess the involvement of miRNA in the inflammation-related carcinogenesis, sphere-forming ability, expression of colon cancer stemness markers, and stability of fascin protein via the proteasome using tough decoy RNA technique.

Results

We found that 17 miRNAs including miR-146a were upregulated and 16 miRNAs were downregulated in FPCKpP1-4 adenocarcinoma cells. We revealed that miR-146a in the adenocarcinoma cells brought about acquisition of sphere formation, cancer stemness, and inhibition of proteasomal degradation of the fascin protein.

Conclusions

We found that stable fascin expression is brought about via the inhibition of proteasome degradation by miR-146a in the process of a chronic inflammation-related colon carcinogenesis.

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References

  1. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66:683–91.

    Article  PubMed  Google Scholar 

  2. Johnson CM, Wei C, Ensor JE, Smolenski DJ, Amos CI, Levin B, Berry DA. Meta-analyses of colorectal cancer risk factors. Cancer Causes Control. 2013;24:1207–22.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.

    Article  PubMed  CAS  Google Scholar 

  4. Tarmin L, Yin J, Harpaz N, Kozam M, Noordzij J, Antonio LB, Jiang HY, Chan O, Cymes K, Meltzer SJ. Adenomatous polyposis coli gene mutations in ulcerative colitis-associated dysplasias and cancers versus sporadic colon neoplasms. Cancer Res. 1995;55:2035–8.

    PubMed  CAS  Google Scholar 

  5. Burmer GC, Levine DS, Kulander BG, Haggitt RC, Rubin CE, Rabinovitch PS. c-Ki-ras mutations in chronic ulcerative colitis and sporadic colon carcinoma. Gastroenterology. 1990;99:416–20.

    Article  PubMed  CAS  Google Scholar 

  6. Baker SJ, Preisinger AC, Jessup JM, Paraskeva C, Markowitz S, Willson JK, Hamilton S, Vogelstein B. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 1990;50:7717–22.

    PubMed  CAS  Google Scholar 

  7. Carethers JM, Jung BH. Genetics and genetic biomarkers in sporadic colorectal cancer. Gastroenterology. 2015;149:1177–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Chaubert P, Benhattar J, Saraga E, Costa J. K-ras mutations and p53 alterations in neoplastic and nonneoplastic lesions associated with longstanding ulcerative colitis. Am J Pathol. 1994;144:767–75.

    PubMed  PubMed Central  CAS  Google Scholar 

  9. Connelly TM, Berg AS, Harris DL 3rd, Brinton DL, Hegarty JP, Deiling SM, Stewart DB, Koltun WA. Ulcerative colitis neoplasia is not associated with common inflammatory bowel disease single-nucleotide polymorphisms. Surgery. 2014;156:253–62.

    Article  PubMed  Google Scholar 

  10. Okada F, Kawaguchi T, Habelhah H, Kobayashi T, Tazawa H, Takeichi N, Kitagawa T, Hosokawa M. Conversion of human colonic adenoma cells to adenocarcinoma cells through inflammation in nude mice. Lab Investig. 2000;80:1617–28.

    Article  PubMed  CAS  Google Scholar 

  11. Tazawa H, Kawaguchi T, Kobayashi T, Kuramitsu Y, Wada S, Satomi Y, Nishino H, Kobayashi M, Kanda Y, Osaki M, Kitagawa T, Hosokawa M, Okada F. Chronic inflammation-derived nitric oxide causes conversion of human colonic adenoma cells into adenocarcinoma cells. Exp Cell Res. 2013;319:2835–44.

    Article  PubMed  CAS  Google Scholar 

  12. Kanda Y, Kawaguchi T, Kuramitsu Y, Kitagawa T, Kobayashi T, Takahashi N, Tazawa H, Habelhah H, Hamada J, Kobayashi M, Hirahata M, Onuma K, Osaki M, Nakamura K, Kitagawa T, Hosokawa M, Okada F. Fascin regulates chronic inflammation-related human colon carcinogenesis by inhibiting cell anoikis. Proteomics. 2014;14:1031–41.

    Article  PubMed  CAS  Google Scholar 

  13. Kanda Y, Osaki M, Okada F. Chemopreventive Strategies for inflammation-related carcinogenesis: Current status and future direction. Int J Mol Sci. 2017;18:E867.

    Article  PubMed  Google Scholar 

  14. Okada F. Beyond foreign-body-induced carcinogenesis: impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression. Int J Cancer. 2007;121:2364–72.

    Article  PubMed  CAS  Google Scholar 

  15. Kawaguchi T, Miyaki M, Masui T, Watanabe M, Ohta H, Maruyama M, Utakoji T, Kitagawa T. Establishment and characterization of an epithelial cell line with quasi-normal chromosomes from a tubular adenoma of a familial polyposis coli patient. Jpn J Cancer Res. 1991;82:138–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Okayama H, Schetter AJ, Harris CC. MicroRNAs and inflammation in the pathogenesis and progression of colon cancer. Dig Dis. 2012;30(Suppl 2):9–15.

    Article  PubMed  Google Scholar 

  17. Wu F, Zikusoka M, Trindade A, Dassopoulos T, Harris ML, Bayless TM, Brant SR, Chakravarti S, Kwon JH. MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2 alpha. Gastroenterology. 2008;135:1624–35.

    Article  PubMed  CAS  Google Scholar 

  18. Iwamoto H, Kanda Y, Sejima T, Osaki M, Okada F, Takenaka A. Serum miR-210 as a potential biomarker of early clear cell renal cell carcinoma. Int J Oncol. 2014;44:53–8.

    Article  PubMed  CAS  Google Scholar 

  19. Kanda Y, Osaki M, Onuma K, Sonoda A, Kobayashi M, Hamada J, Nicolson GL, Ochiya T, Okada F. Amigo2-upregulation in tumour cells facilitates their attachment to liver endothelial cells resulting in liver metastases. Sci Rep. 2017;7:43567.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kitajima S, Kohno S, Kondoh A, Sasaki N, Nishimoto Y, Li F, Mohammed A, Muranaka H, Nagatani N, Suzuki M, Kido Y, Takahashi C. Undifferentiated state induced by Rb-p53 double inactivation in mouse thyroid neuroendocrine cells and embryonic fibroblasts. Stem Cells. 2015;33:1657–69.

    Article  PubMed  CAS  Google Scholar 

  21. Vermeulen L, Todaro M, de Sousa Mello F, Sprick F, Kemper MR, Perez Alea K, Richel M, Stassi DJ, Medema G. JP. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci USA. 2008;105:13427–32.

    Article  PubMed  Google Scholar 

  22. Haraguchi T, Ozaki Y, Iba H. Vectors expressing efficient RNA decoys achieve the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res. 2009;37:e43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Goldberg AL. Development of proteasome inhibitors as research tools and cancer drugs. J Cell Biol. 2012;199:583–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Lin J, Welker NC, Zhao Z, Li Y, Zhang J, Reuss SA, Zhang X, Lee H, Liu Y, Bronner MP. Novel specific microRNA biomarkers in idiopathic inflammatory bowel disease unrelated to disease activity. Mod Pathol. 2014;27:602–8.

    Article  PubMed  CAS  Google Scholar 

  25. Qualtrough D, Smallwood K, Littlejohns D, Pignatelli M. The actin-bundling protein fascin is overexpressed in inflammatory bowel disease and may be important in tissue repair. BMC Gastroenterol. 2011;11:14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Chen MB, Wei MX, Han JY, Wu XY, Li C, Wang J, Shen W, Lu PH. MicroRNA-451 regulates AMPK/mTORC1 signaling and fascin1 expression in HT-29 colorectal cancer. Cell Signal. 2014;26:102–9.

    Article  PubMed  CAS  Google Scholar 

  27. Li YQ, Lu JH, Bao XM, Wang XF, Wu JH, Hong WQ. MiR-24 functions as a tumor suppressor in nasopharyngeal carcinoma through targeting FSCN1. J Exp Clin Cancer Res. 2015;34:130.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Kano M, Seki N, Kikkawa N, Fujimura L, Hoshino I, Akutsu Y, Chiyomaru T, Enokida H, Nakagawa M, Matsubara H. miR-145, miR-133a and miR-133b: tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer. 2010;127:2804–14.

    Article  PubMed  CAS  Google Scholar 

  29. Liu R, Liao J, Yang M, Sheng J, Yang H, Wang Y, Pan E, Guo W, Pu Y, Kim SJ, Yin L. The cluster of miR-143 and miR-145 affects the risk for esophageal squamous cell carcinoma through co-regulating fascin homolog 1. PLoS One. 2012;7:e33987.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Li Y, Gao Y, Xu Y, Ma H, Yang M. Down-regulation of miR-326 is associated with poor prognosis and promotes growth and metastasis by targeting FSCN1 in gastric cancer. Growth Factors. 2015;33:267–74.

    Article  PubMed  CAS  Google Scholar 

  31. Zhang M, Dong BB, Lu M, Zheng MJ, Chen H, Ding JZ, Xu AM, Xu YH. miR-429 functions as a tumor suppressor by targeting FSCN1 in gastric cancer cells. Onco Targets Ther. 2016;9:1123–33.

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Xiao P, Liu W, Zhou H. miR-200b inhibits migration and invasion in non-small cell lung cancer cells via targeting FSCN1. Mol Med Rep. 2016;14:1835–40.

    Article  PubMed  CAS  Google Scholar 

  33. Liu Y, Hong W, Zhou C, Jiang Z, Wang G, Wei G, Li X. miR-539 inhibits FSCN1 expression and suppresses hepatocellular carcinoma migration and invasion. Oncol Rep. 2017;37:2593–602.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Yu S, Xie H, Zhang J, Wang D, Song Y, Zhang S, Zheng S, Wang J. MicroRNA663 suppresses the proliferation and invasion of colorectal cancer cells by directly targeting FSCN1. Mol Med Rep. 2017;16:9707–14.

    Article  PubMed  CAS  Google Scholar 

  35. Mani A, Gelmann EP. The ubiquitin-proteasome pathway and its role in cancer. J Clin Oncol. 2005;23:4776–89.

    Article  PubMed  CAS  Google Scholar 

  36. Fuchs SY. The role of ubiquitin-proteasome pathway in oncogenic signaling. Cancer Biol Ther. 2002;1:337–41.

    Article  PubMed  CAS  Google Scholar 

  37. Leung CO, Deng W, Ye TM, Ngan HY, Tsao SW, Cheung AN, Pang RT, Yeung WS. miR-135a leads to cervical cancer cell transformation through regulation of beta-catenin via a SIAH1-dependent ubiquitin proteosomal pathway. Carcinogenesis. 2014;35:1931–40.

    Article  PubMed  CAS  Google Scholar 

  38. Sears R, Leone G, DeGregori J, Nevins JR. Ras enhances Myc protein stability. Mol Cell. 1999;3:169–79.

    Article  PubMed  CAS  Google Scholar 

  39. McClurg UL, Robson CN. Deubiquitinating enzymes as oncotargets. Oncotarget. 2015;6:9657–68.

    PubMed  PubMed Central  Google Scholar 

  40. Voutsadakis IA. Proteasome expression and activity in cancer and cancer stem cells. Tumour Biol. 2017;39:1010428317692248.

    Article  PubMed  Google Scholar 

  41. Hwang WL, Jiang JK, Yang SH, Huang TS, Lan HY, Teng HW, Yang CY, Tsai YP, Lin CH, Wang HW, Yang MH. MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells. Nat Cell Biol. 2014;16:268–80.

    Article  PubMed  CAS  Google Scholar 

  42. Lenos KJ, Vermeulen L. Cancer stem cells don’t waste their time cleaning-low proteasome activity, a marker for cancer stem cell function. Ann Transl Med. 2016;4:519.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Abbaszadegan MR, Bagheri V, Razavi MS, Momtazi AA, Sahebkar A, Gholamin M. Isolation, identification, and characterization of cancer stem cells: a review. J Cell Physiol. 2017;232:2008–18.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Drs. Toshiaki Inoue and Shunsuke Kitajima for critical advice. This work was supported in part by a Grant-in-Aid to FO from the Japanese Ministry of Education, Culture, Sports, Science and Technology (26460472 and 17K08761); the Research Grant of the Princess Takamatsu Cancer Research Fund. This work was also supported in part by a Grant-in-Aid to MO from the Takeda Science Foundation. YK was supported by the Japan Society for the Promotion of Science (15J07285, Research Fellowship for Young Scientists).

Author information

Authors and Affiliations

  1. Division of Pathological Biochemistry, Tottori University Faculty of Medicine, 86 Nishicho, Yonago, 683-8503, Japan

    Yusuke Kanda, Mitsuhiko Osaki, Kunishige Onuma & Futoshi Okada

  2. Japanese Foundation for Cancer Research, Cancer Institute, Tokyo, 135-8550, Japan

    Tokuichi Kawaguchi & Tomoyuki Kitagawa

  3. Chromosome Engineering Research Center, Tottori University, Yonago, 683-8503, Japan

    Mitsuhiko Osaki & Futoshi Okada

  4. Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Takahiro Ochiya

Authors
  1. Yusuke Kanda
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  2. Tokuichi Kawaguchi
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  3. Mitsuhiko Osaki
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  4. Kunishige Onuma
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  5. Takahiro Ochiya
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  6. Tomoyuki Kitagawa
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  7. Futoshi Okada
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Contributions

FO designed and arranged all of the experiments; YK and KO performed experiments and data analysis; TK, MO, TO, and TK contributed to discussion of the experimental design and interpretation of the results; YK, MO, and FO wrote the manuscript.

Corresponding author

Correspondence to Futoshi Okada.

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The authors declare no competing financial interests.

Additional information

Responsible Editor: John Di Battista.

Electronic supplementary material

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Supplementary Figure 1

: MiR-146a expression in pro-inflammatory cytokine-treated FPCK-1-1 cells. Levels of miR-146a were measured in FPCK-1-1 cells treated with 100 ng/mL TNF-ɑ or 10 ng/mL IL-1 β for 24 h. Bar graphs show mean ± SD (n = 5 in each group). (PDF 11 KB)

Supplementary Figure 2

. MG-132 stabilizes fascin protein in both FPCK-1-1 cells and FPCKpP1-4 cells. FPCK-1-1 and FPCKpP1-4 cells were treated with 10 µM MG-132 for 12 h and the fascin protein was detected by Western blot (top). The results were quantified and normalized to non-treated FPCK-1-1 cells (bottom). (PDF 102 KB)

Supplementary material 3 (DOCX 38 KB)

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Kanda, Y., Kawaguchi, T., Osaki, M. et al. Fascin protein stabilization by miR-146a implicated in the process of a chronic inflammation-related colon carcinogenesis model. Inflamm. Res. 67, 839–846 (2018). https://doi.org/10.1007/s00011-018-1175-2

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  • DOI: https://doi.org/10.1007/s00011-018-1175-2

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