Skip to main content

Advertisement

SpringerLink
Log in

MicroRNA-10a is Overexpressed in Human Pancreatic Cancer and Involved in Its Invasiveness Partially via Suppression of the HOXA1 Gene

  • Pancreatic Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

There is increasing evidence that microRNAs are differentially expressed in many types of cancers. Despite progress in analyses of microRNAs in several types of cancers, the functional contributions of microRNAs to pancreatic cancer remain unclear.

Methods

In the present study, the expression levels of specific microRNAs identified by microarray analyses were examined in a panel of 15 pancreatic cancer cell lines. We then investigated the functional roles of these microRNAs in the proliferation and invasion of pancreatic cancer cells.

Results

Based on the microarray data, we found frequent and marked overexpression of miR-10a, miR-92, and miR-17-5p in pancreatic cancer cell lines. Microdissection analyses revealed that miR-10a was overexpressed in pancreatic cancer cells isolated from a subset of primary tumors (12 of 20, 60%) compared with precursor lesions and normal ducts (P < .01). In vitro experiments revealed that miR-10a inhibitors decreased the invasiveness of pancreatic cancer cells (P < .01), but had no effect on their proliferation. Inhibition of HOXA1, a target of miR-10a, promoted the invasiveness of pancreatic cancer cells (P < .01).

Conclusions

The present data suggest that miR-10a is overexpressed in a subset of pancreatic cancers and is involved in the invasive potential of pancreatic cancer cells partially via suppression of HOXA1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

FIG. 1
FIG. 2
FIG. 3
FIG. 4

Similar content being viewed by others

REFERENCES

  1. Hirata K, Egawa S, Kimura Y, Nobuoka T, Oshima H, Katsuramaki T, et al. Current status of surgery for pancreatic cancer. Dig Surg. 2007;24:137–47.

    Article  PubMed  Google Scholar 

  2. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin. 2003;53:5–26.

    Article  PubMed  Google Scholar 

  3. Hawes RH, Xiong Q, Waxman I, Chang KJ, Evans DB, Abbruzzese JL. A multispecialty approach to the diagnosis and management of pancreatic cancer. Am J Gastroenterol. 2000;95:17–31.

    Article  PubMed  CAS  Google Scholar 

  4. Matsuno S, Egawa S, Fukuyama S, Motoi F, Sunamura M, Isaji S, et al. Pancreatic cancer registry in Japan: 20 years of experience. Pancreas. 2004;28:219–30.

    Article  PubMed  Google Scholar 

  5. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350:1200–10.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  7. Lau NC, Lim LP, Weinstein EG, Bartel DP. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science. 2001;294:858–62.

    Article  PubMed  CAS  Google Scholar 

  8. Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science. 2001;294:862–4.

    Article  PubMed  CAS  Google Scholar 

  9. Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell. 2003;113:673–6.

    Article  PubMed  CAS  Google Scholar 

  10. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, et al. RAS is regulated by the let-7 microRNA family. Cell. 2005;120:635–47.

    Article  PubMed  CAS  Google Scholar 

  11. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002;99:15524–9.

    Article  PubMed  CAS  Google Scholar 

  12. Michael MZ, SM OC, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res. 2003;1:882–91.

    PubMed  CAS  Google Scholar 

  13. Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A. High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosomes Cancer. 2004;39:167–9.

    Article  PubMed  CAS  Google Scholar 

  14. Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005;65:9628–32.

    Article  PubMed  CAS  Google Scholar 

  15. He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435:828–33.

    Article  PubMed  CAS  Google Scholar 

  16. Liang RQ, Li W, Li Y, Tan CY, Li JX, Jin YX, et al. An oligonucleotide microarray for microRNA expression analysis based on labeling RNA with quantum dot and nanogold probe. Nucleic Acids Res. 2005;33:e17.

    Article  PubMed  Google Scholar 

  17. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8.

    Article  PubMed  CAS  Google Scholar 

  18. Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297:1901–8.

    Article  PubMed  CAS  Google Scholar 

  19. Szafranska AE, Davison TS, John J, Cannon T, Sipos B, Maghnouj A, et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene. 2007;26:4442–52.

    Article  PubMed  CAS  Google Scholar 

  20. Calvo R, West J, Franklin W, Erickson P, Bemis L, Li E, et al. Altered HOX and WNT7A expression in human lung cancer. Proc Natl Acad Sci USA. 2000;97:12776–81.

    Article  PubMed  CAS  Google Scholar 

  21. Tsou JA, Galler JS, Siegmund KD, Laird PW, Turla S, Cozen W, et al. Identification of a panel of sensitive and specific DNA methylation markers for lung adenocarcinoma. Mol Cancer. 2007;6:70.

    Article  PubMed  Google Scholar 

  22. Kang GH, Lee S, Cho NY, Gandamihardja T, Long TI, Weisenberger DJ, et al. DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest. 2008;88:161–70.

    Article  PubMed  CAS  Google Scholar 

  23. Sato N, Mizumoto K, Beppu K, Maehara N, Kusumoto M, Nabae T, et al. Establishment of a new human pancreatic cancer cell line, NOR-P1, with high angiogenic activity and metastatic potential. Cancer Lett. 2000;155:153–61.

    Article  PubMed  CAS  Google Scholar 

  24. Furukawa T, Duguid WP, Rosenberg L, Viallet J, Galloway DA, Tsao MS. Long-term culture and immortalization of epithelial cells from normal adult human pancreatic ducts transfected by the E6E7 gene of human papilloma virus 16. Am J Pathol. 1996;148:1763–70.

    PubMed  CAS  Google Scholar 

  25. Ohuchida K, Mizumoto K, Murakami M, Qian LW, Sato N, Nagai E, et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 2004;64:3215–22.

    Article  PubMed  CAS  Google Scholar 

  26. Ohuchida K, Mizumoto K, Ishikawa N, Fujii K, Konomi H, Nagai E, et al. The role of S100A6 in pancreatic cancer development and its clinical implication as a diagnostic marker and therapeutic target. Clin Cancer Res. 2005;11:7785–93.

    Article  PubMed  CAS  Google Scholar 

  27. Ohuchida K, Mizumoto K, Fujita H, Yamaguchi H, Konomi H, Nagai E, et al. Sonic hedgehog is an early developmental marker of intraductal papillary mucinous neoplasms: clinical implications of mRNA levels in pancreatic juice. J Pathol. 2006;210:42–8.

    Article  PubMed  CAS  Google Scholar 

  28. Ohuchida K, Mizumoto K, Egami T, Yamaguchi H, Fujii K, Konomi H, et al. S100P is an early developmental marker of pancreatic carcinogenesis. Clin Cancer Res. 2006;12:5411–6.

    Article  PubMed  CAS  Google Scholar 

  29. Zhang L, Mizumoto K, Sato N, Ogawa T, Kusumoto M, Niiyama H, et al. Quantitative determination of apoptotic death in cultured human pancreatic cancer cells by propidium iodide and digitonin. Cancer Lett. 1999;142:129–37.

    Article  PubMed  CAS  Google Scholar 

  30. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103:2257–61.

    Article  PubMed  CAS  Google Scholar 

  31. Weiss FU, Marques IJ, Woltering JM, Vlecken DH, Aghdassi A, Partecke LI, et al. Retinoic acid receptor antagonists inhibit miR-10a expression and block metastatic behavior of pancreatic cancer. Gastroenterology. 2009;137:2136–45 e1–7.

    PubMed  Google Scholar 

  32. Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN, et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol. 2001;25:579–86.

    Article  PubMed  CAS  Google Scholar 

  33. Garzon R, Pichiorri F, Palumbo T, Iuliano R, Cimmino A, Aqeilan R, et al. MicroRNA fingerprints during human megakaryocytopoiesis. Proc Natl Acad Sci USA. 2006;103:5078–83.

    Article  PubMed  CAS  Google Scholar 

  34. Hwang HW, Wentzel EA, Mendell JT. Cell-cell contact globally activates microRNA biogenesis. Proc Natl Acad Sci USA. 2009;106:7016–21.

    Article  PubMed  CAS  Google Scholar 

  35. Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 2007;449:682–8.

    Article  PubMed  CAS  Google Scholar 

  36. Mertani HC, Zhu T, Goh EL, Lee KO, Morel G, Lobie PE. Autocrine human growth hormone (hGH) regulation of human mammary carcinoma cell gene expression. Identification of CHOP as a mediator of hGH-stimulated human mammary carcinoma cell survival. J Biol Chem. 2001;276:21464–75.

    Article  PubMed  CAS  Google Scholar 

  37. Zhang X, Zhu T, Chen Y, Mertani HC, Lee KO, Lobie PE. Human growth hormone-regulated HOXA1 is a human mammary epithelial oncogene. J Biol Chem. 2003;278:7580–90.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENT

Supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a grant from the Kato Memorial Bioscience Foundation. We are grateful to Emiko Manabe, Midori Sato, and Miyuki Omori (Department of Surgery and Oncology, Kyushu University) for skillful technical assistance.

Author information

Authors and Affiliations

  1. Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Kenoki Ohuchida MD, PhD, Kazuhiro Mizumoto MD, PhD, Cui Lin MD, PhD, Takao Ohtsuka MD, PhD, Norihiro Sato MD, PhD, Hiroki Toma MD, PhD, Masafumi Nakamura MD, PhD, Eishi Nagai MD, PhD & Masao Tanaka MD, PhD

  2. Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Kenoki Ohuchida MD, PhD & Makoto Hashizume MD, PhD

  3. Kyushu University Hospital Cancer Center, Fukuoka, Japan

    Kazuhiro Mizumoto MD, PhD

  4. Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Hiroshi Yamaguchi MD, PhD

  5. Department of Pathology, Saitama Medical University International Medical Center, Saitama, Japan

    Hiroshi Yamaguchi MD, PhD

Authors
  1. Kenoki Ohuchida MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuhiro Mizumoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cui Lin MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroshi Yamaguchi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takao Ohtsuka MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Norihiro Sato MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroki Toma MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masafumi Nakamura MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eishi Nagai MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Makoto Hashizume MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masao Tanaka MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kenoki Ohuchida MD, PhD or Kazuhiro Mizumoto MD, PhD.

ELECTRONIC SUPPLEMENTARY MATERIAL

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ohuchida, K., Mizumoto, K., Lin, C. et al. MicroRNA-10a is Overexpressed in Human Pancreatic Cancer and Involved in Its Invasiveness Partially via Suppression of the HOXA1 Gene. Ann Surg Oncol 19, 2394–2402 (2012). https://doi.org/10.1245/s10434-012-2252-3

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-012-2252-3

Keywords

Search

Navigation