Skip to main content

Advertisement

Log in

Microarray analyses reveal liver metastasis-related genes in metastatic colorectal cancer cell model

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

To study the molecular mechanisms of colorectal cancer liver metastasis.

Methods

Cecal wall implantation was performed in nude mice to subclone a highly liver metastatic human colorectal cancer clone (SW1116-M) from SW1116. In vivo and in vitro assays were adopted to confirm the proliferation and metastasis potential. The human tumor metastasis PCR microarrays were used to analyze the differential gene expressions. The results were confirmed further by real-time quantitative PCR.

Results

SW1116-M and SW1116-S5, two human colon cancer cell clones with different metastatic potential, were subcloned from SW1116. In SW1116-M, in vitro invasion, migration and in vivo metastatic potential were higher, and in vitro proliferation rate was lower than SW1116-S5. In tumor metastasis PCR microarray, 24 genes related to cell invading, adhesion, cellular growth and differentiation were found with a twofold difference between SW1116-S5 and SW1116-M. Sixteen of these, including E-cadherins, MTSS1, TRAIL and TRPM1, were up-regulated; eight genes including cathepsin L, EphB2, HGF, MET, MCAM and RORβ were down-regulated.

Conclusions

We have established a highly liver metastatic clone. The subsequent metastasis PCR microarray analysis identified a procedure of cellular differentiation and mesenchymal to epithelial transition (MET) in liver metastasis. The colonization to from macrometastasis is not a switch from cell cycle arrest but a result of cell differentiation and MET.

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

Access this article

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
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Abdalla EK, Hicks ME, Vauthey JN (2001) Portal vein embolization: rationale, technique and future prospects. Br J Surg 88:165–175

    Article  PubMed  CAS  Google Scholar 

  • Anjomshoaa A, Nasri S, Humar B, McCall JL, Chatterjee A, Yoon HS, McNoe L, Black MA, Reeve AE (2009) Slow proliferation as a biological feature of colorectal cancer metastasis. Br J Cancer 101:822–828

    Article  PubMed  CAS  Google Scholar 

  • Arakaki N, Kajihara T, Arakaki R, Ohnishi T, Kazi JA, Nakashima H, Daikuhara Y (1999) Involvement of oxidative stress in tumor cytotoxic activity of hepatocyte growth factor/scatter factor. J Biol Chem 274:13541–13546

    Article  PubMed  CAS  Google Scholar 

  • Brew K, Nagase H (2010) The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 1803:55–71

    Article  PubMed  CAS  Google Scholar 

  • Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345

    Article  PubMed  CAS  Google Scholar 

  • Delektorskaya VV, Perevoshchikov AG, Golovkov DA, Kushlinskii NE (2005) Expression of E-cadherin, beta-catenin, and CD-44v6 cell adhesion molecules in primary tumors and metastases of colorectal adenocarcinoma. Bull Exp Biol Med 139(6):706–710

    Article  PubMed  CAS  Google Scholar 

  • Deves C, Renck D, Garicochea B, da Silva VD, Giulianni Lopes T, Fillman H, Fillman L, Lunardini S, Basso LA, Santos DS, Batista EL Jr (2011) Analysis of select members of the E26 (ETS) transcription factors family in colorectal cancer. Virchows Arch 458(4):421–430

    Article  PubMed  CAS  Google Scholar 

  • Dyer MJ, MacFarlane M, Cohen GM (2007) Barriers to effective TRAIL-targeted therapy of malignancy. J Clin Oncol 25(28):4505–4506

    Article  PubMed  Google Scholar 

  • Foveau B, Leroy C, Ancot F, Deheuninck J, Ji Z, Fafeur V et al (2007) Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor. Cell Death Differ 14:752–764

    Article  PubMed  CAS  Google Scholar 

  • Ginos MA, Page GP, Michalowicz BS, Patel KJ, Volker SE, Pambuccian SE, Ondrey FG, Adams GL, Gaffney PM (2004) Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck. Cancer Res 64(1):55–63

    Article  PubMed  CAS  Google Scholar 

  • Gocheva V, Joyce JA (2007) Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle 6(1):60–64

    Article  PubMed  CAS  Google Scholar 

  • Gocheva V, Zeng W, Ke D, Klimstra D, Reinheckel T, Peters C, Hanahan D, Joyce JA (2006) Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev 20(5):543–556

    Article  PubMed  CAS  Google Scholar 

  • Goulet B, Sansregret L, Leduy L, Bogyo M, Weber E, Chauhan SS, Nepveu A (2007) Increased expression and activity of nuclear cathepsin L in cancer cells suggests a novel mechanism of cell transformation. Mol Cancer Res 5(9):899–907

    Article  PubMed  CAS  Google Scholar 

  • Han YC, Yu YP, Nelson J, Wu C, Wang H, Michalopoulos GK, Luo JH (2010) Interaction of integrin-linked kinase and miniature chromosome maintenance 7-mediating integrin {alpha}7 induced cell growth suppression. Cancer Res 70(11):4375–4384

    Article  PubMed  CAS  Google Scholar 

  • Heinzle C, Gsur A, Hunjadi M, Erdem Z, Gauglhofer C, Stättner S, Karner J, Klimpfinger M, Wrba F, Reti A, Hegedus B, Baierl A, Grasl-Kraupp B, Holzmann K, Grusch M, Berger W, Marian B (2012) Differential effects of polymorphic alleles of FGF receptor 4 on colon cancer growth and metastasis. Cancer Res 72(22):5767–5777. doi:10.1158/0008-5472

    Article  PubMed  CAS  Google Scholar 

  • Hezel AF, Deshpande V, Zimmerman SM, Contino G, Alagesan B, O’Dell MR, Rivera LB, Harper J, Lonning S, Brekken RA, Bardeesy N (2012) TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression. Cancer Res 72(18):4840–4845

    Article  PubMed  CAS  Google Scholar 

  • Hill A, McFarlane S, Mulligan K, Gillespie H, Draffin JE, Trimble A, Ouhtit A, Johnston PG, Harkin DP, McCormick D, Waugh DJ (2006) Cortactin underpins CD44-promoted invasion and adhesion of breast cancer cells to bone marrow endothelial cells. Oncogene 25(45):6079–6091

    Article  PubMed  CAS  Google Scholar 

  • Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics. CA Cancer J Clin 57:43–66

    Article  PubMed  Google Scholar 

  • Kartenbeck J, Haselmann U, Gassler N (2005) Synthesis of junctional proteins in metastasizing colon cancer cells. Eur J Cell Biol 84:417–430

    Article  PubMed  CAS  Google Scholar 

  • Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52–67

    Article  PubMed  CAS  Google Scholar 

  • Klein CA, Blankenstein TJ, Schmidt-Kittler O, Petronio M, Polzer B, Stoecklein NH, Riethmüller G (2002) Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 360:683–689

    Article  PubMed  CAS  Google Scholar 

  • Langenskiöld M, Holmdahl L, Falk P, Angenete E, Ivarsson ML (2008) Increased TGF-beta 1 protein expression in patients with advanced colorectal cancer. J Surg Oncol 97(5):409–415

    Article  PubMed  Google Scholar 

  • Leibovitz A, Stinson JC, McCombs WB 3rd, McCoy CE, Mazur KC, Mabry ND (1976) Classification of human colorectal adenocarcinoma cell lines. Cancer Res 36:4562–4569

    PubMed  CAS  Google Scholar 

  • Lin J, Liu J, Wang Y, Zhu J, Zhou K, Smith N, Zhan X (2005) Differential regulation of cortactin and N-WASP-mediated actin polymerization by missing in metastasis (MIM) protein. Oncogene 24(12):2059–2066

    Article  PubMed  CAS  Google Scholar 

  • Liu K, Wang G, Ding H, Chen Y, Yu G, Wang J (2010) Downregulation of metastasis suppressor 1 (MTSS1) is associated with nodal metastasis and poor outcome in Chinese patients with gastric cancer. BMC Cancer 10:428–437

    Article  PubMed  Google Scholar 

  • Merlos-Sua′rez A, Barriga FM, Jung P, Iglesias M, Ce′spedes MV, Rossell D, Sevillano M, Hernando-Momblona X, da Silva-Diz V, Mun˜oz P, Clevers H, Sancho E, Mangues R, Batlle E (2011) The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 8(5):511–524

    Article  Google Scholar 

  • Miller AJ, Du J, Rowan S, Hershey CL, Widlund HR, Fisher DE (2004) Transcriptional regulation of the melanoma prognostic marker melastatin (TRPM1) by MITF in melanocytes and melanoma. Cancer Res 64(2):509–516

    Article  PubMed  CAS  Google Scholar 

  • Mizuno S, Nakamura T (2007) Hepatocyte growth factor: a regenerative drug for acute hepatitis and liver cirrhosis. Regen Med 2(2):161–170

    Article  PubMed  CAS  Google Scholar 

  • Mizuno S, Matsumoto K, Li MY, Nakamura T (2005) HGF reduces advancing lung fibrosis in mice: a potential role for MMP-dependent myofibroblast apoptosis. FASEB J 19:580–582

    PubMed  Google Scholar 

  • Oshima T, Akaike M, Yoshihara K, Shiozawa M, Yamamoto N, Sato T, Akihito N, Nagano Y, Fujii S, Kunisaki C, Wada N, Rino Y, Tanaka K, Masuda M, Imada T (2008) Overexpression of EphA4 gene and reduced expression of EphB2 gene correlates with liver metastasis in colorectal cancer. Int J Oncol 33(3):573–577

    PubMed  CAS  Google Scholar 

  • Ottaiano A, Napolitano M, Tatangelo F, Acquaviva AM, Ascierto PA, Scala S (2005) Inhibitory effects of anti-CXCR4 antibodies on human colon cancer cells. Cancer Immunol Immunother 54:781–791

    Article  PubMed  CAS  Google Scholar 

  • Parkin DM, Bray F, Ferlay J, Pisani P (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  Google Scholar 

  • Parr C, Jiang WG (2009) Metastasis suppressor 1 (MTSS1) demonstrates prognostic value and anti-metastatic properties in breast cancer. Eur J Cancer 45(9):1673–1683

    Article  PubMed  CAS  Google Scholar 

  • Raggi CC, Cianchi F, Valanzano R, Smith MC, Serio M, Maggi M, Orlando C (2005) Prognostic value of somatostatin receptor subtype 2 expression in colorectal cancer. Regul Pept 132(1–3):23–26

    Article  PubMed  CAS  Google Scholar 

  • Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905–914

    Article  PubMed  CAS  Google Scholar 

  • Sancier F, Dumont A, Sirvent A, Paquay de Plater L, Edmonds T, David G, Jan M, de Montrion C, Coge F, Leonce S, Burbridge M, Bruno A, Boutin JA, Lockhart B, Roche S, Cruzalegui F (2011) Specific oncogenic activity of the Src-family tyrosine kinase c-Yes in colon carcinoma cells. PLoS ONE 6(2):e17237

    Article  PubMed  CAS  Google Scholar 

  • Seki N, Hayakawa Y, Brooks AD, Wine J, Wiltrout RH, Yagita H, Tanner JE, Smyth MJ, Sayers TJ (2003) Tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis is an important endogenous mechanism for resistance to liver metastases in murine renal cancer. Cancer Res 63(1):207–213

    PubMed  CAS  Google Scholar 

  • Shiratsuchi I, Akagi Y, Kawahara A, Kinugasa T, Romeo K, Yoshida T, Ryu Y, Gotanda Y, Kage M, Shirouzu K (2011) Expression of IGF-1 and IGF-1R and their relation to clinicopathological factors in colorectal cancer. Anticancer Res 31(7):2541–2545

    PubMed  CAS  Google Scholar 

  • Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R (2003) All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat Struct Biol 10(10):820–825

    Article  PubMed  CAS  Google Scholar 

  • Wang D, Xu MR, Wang T, Li T, Zhu JW (2011) MTSS1 overexpression correlates with poor prognosis in colorectal cancer. J Gastrointest Surg 15:1205–1212

    Article  PubMed  Google Scholar 

  • Wei HB, Hu BG, Han XY, Zheng ZH, Wei B, Huang JL (2008) Effect of all-trans retinoic acid on drug sensitivity and expression of survivin in LoVo cells. Chin Med J 121(4):331–335

    PubMed  CAS  Google Scholar 

  • Woo YJ, Jang KL (2012) All-trans retinoic acid activates E-cadherin expression via promoter hypomethylation in the human colon carcinoma HCT116 cells. Biochem Biophys Res Commun 425(4):944–999

    Article  PubMed  CAS  Google Scholar 

  • Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ (2008) Direct regulation of TWIST by HIF-1a promotes metastasis. Nat Cell Biol 10(3):295–305

    Article  PubMed  CAS  Google Scholar 

  • Zabouo G, Imbert AM, Jacquemier J, Finetti P, Moreau T, Esterni B, Birnbaum D, Bertucci F, Chabannon C (2009) CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines. Breast Cancer Res 11(1):R1

    Article  PubMed  Google Scholar 

  • Zeng Q, Li W, Lu D, Wu Z, Duan H, Luo Y, Feng J, Yang D, Fu L, Yan X (2012) CD146, an epithelial-mesenchymal transition inducer, is associated with triple-negative breast cancer. Proc Natl Acad Sci USA 109(4):1127–1132

    Article  PubMed  CAS  Google Scholar 

  • Zhu ZH, Yu YP, Zheng ZL, Song Y, Xiang GS, Nelson J, Michalopoulos G, Luo JH (2010) Integrin alpha 7 interacts with high temperature requirement A2 (HtrA2) to induce prostate cancer cell death. Am J Pathol 177(3):1176–1186

    Article  PubMed  CAS  Google Scholar 

  • Zigler M, Villares GJ, Dobroff AS, Wang H, Huang L, Braeuer RR, Kamiya T, Melnikova VO, Song R, Friedman R, Alani RM, Bar-Eli M (2011) Expression of Id-1 is regulated by MCAM/MUC18: a missing link in melanoma progression. Cancer Res 71(10):3494–3504

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study is sponsored by the Science, Education and Health Foundation of Soochow City (SWKQ0916).

Conflict of interest

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, and there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Ren Zhao or Chun-gen Xing.

Additional information

L. Chen and Q. Chen contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, Q., Chen, L., Zhao, R. et al. Microarray analyses reveal liver metastasis-related genes in metastatic colorectal cancer cell model. J Cancer Res Clin Oncol 139, 1169–1178 (2013). https://doi.org/10.1007/s00432-013-1424-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-013-1424-2

Keywords

Navigation