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Published in: Clinical & Experimental Metastasis 8/2011

01-12-2011 | Research Paper

Silencing of CD44 by siRNA suppressed invasion, migration and adhesion to matrix, but not secretion of MMPs, of cholangiocarcinoma cells

Authors: Pongsanat Pongcharoen, Artit Jinawath, Rutaiwan Tohtong

Published in: Clinical & Experimental Metastasis | Issue 8/2011

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Abstract

We studied the expression pattern and the role of CD44 in regulating the malignant behavior of two cholangiocarcinoma (CCA) cell lines which expressed different levels of CD44 using the siRNA technique. KKU-100, the high CD44 expresser, exhibited a high degree of in vitro invasiveness, migration and adhesion to Matrigel compared to HuCCA-1. Silencing of CD44 by siRNA did not have a significant effect on cell proliferation. However, in vitro invasiveness, directional migration (chemotaxis) and adhesion to Matrigel were markedly reduced in both cell lines, although chemokinesis and MMP secretion were variable, demonstrating the distinct functional role and requirement for CD44 in different cellular activities and in different cell types. In addition, immunohistochemical analysis suggested that CD44 may be involved in the differentiation process or tumor progression, depending on the macroscopic type of CCA. Taken together, our data indicate that CD44 is an important requirement for the invasive phenotype of CCA cells, although the role that CD44 plays may vary depending on the CCA type and the cellular activity in which it is engaged.
Literature
1.
go back to reference Anderson CD, Pinson CW, Berlin J et al (2004) Diagnosis and treatment of cholangiocarcinoma. Oncologist 9(1):43–57PubMedCrossRef Anderson CD, Pinson CW, Berlin J et al (2004) Diagnosis and treatment of cholangiocarcinoma. Oncologist 9(1):43–57PubMedCrossRef
2.
3.
4.
go back to reference Vatanasapt V, Sriamporn S, Vatanasapt P (2002) Cancer control in Thailand. Jpn J Clin Oncol 32(1):S82–S91PubMedCrossRef Vatanasapt V, Sriamporn S, Vatanasapt P (2002) Cancer control in Thailand. Jpn J Clin Oncol 32(1):S82–S91PubMedCrossRef
5.
go back to reference Yamasaki S (2003) Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J Hepatobiliary Pancreat Surg 10(4):288–291PubMedCrossRef Yamasaki S (2003) Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J Hepatobiliary Pancreat Surg 10(4):288–291PubMedCrossRef
6.
go back to reference Yamamoto Y, Shimada K, Sakamoto Y et al (2009) Clinicopathological characteristics of intrahepatic cholangiocellular carcinoma presenting intrahepatic bile duct growth. J Surg Oncol 99(3):161–165PubMedCrossRef Yamamoto Y, Shimada K, Sakamoto Y et al (2009) Clinicopathological characteristics of intrahepatic cholangiocellular carcinoma presenting intrahepatic bile duct growth. J Surg Oncol 99(3):161–165PubMedCrossRef
7.
go back to reference Nakanuma Y, Harada K, Ishikawa A et al (2003) Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 10(4):265–281PubMedCrossRef Nakanuma Y, Harada K, Ishikawa A et al (2003) Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 10(4):265–281PubMedCrossRef
8.
go back to reference Guglielmi A, Ruzzenente A, Campagnaro T et al (2009) Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection. World J Surg 33(6):1247–1254PubMedCrossRef Guglielmi A, Ruzzenente A, Campagnaro T et al (2009) Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection. World J Surg 33(6):1247–1254PubMedCrossRef
9.
go back to reference Zen Y, Fujii T, Itatsu K et al (2006) Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreas. Hepatology 44(5):1333–1343PubMedCrossRef Zen Y, Fujii T, Itatsu K et al (2006) Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreas. Hepatology 44(5):1333–1343PubMedCrossRef
10.
go back to reference Jinawath N, Chamgramol Y, Furukawa Y et al (2006) Comparison of gene expression profiles between Opisthorchis viverrini and non-Opisthorchis viverrini associated human intrahepatic cholangiocarcinoma. Hepatology 44(4):1025–1038PubMedCrossRef Jinawath N, Chamgramol Y, Furukawa Y et al (2006) Comparison of gene expression profiles between Opisthorchis viverrini and non-Opisthorchis viverrini associated human intrahepatic cholangiocarcinoma. Hepatology 44(4):1025–1038PubMedCrossRef
11.
12.
13.
go back to reference Marhaba R, Zoller M (2004) CD44 in cancer progression: adhesion, migration and growth regulation. J Mol Histol 35(3):211–231PubMedCrossRef Marhaba R, Zoller M (2004) CD44 in cancer progression: adhesion, migration and growth regulation. J Mol Histol 35(3):211–231PubMedCrossRef
14.
go back to reference Underhill C (1992) CD44: the hyaluronan receptor. J Cell Sci 103(2):293–298PubMed Underhill C (1992) CD44: the hyaluronan receptor. J Cell Sci 103(2):293–298PubMed
15.
go back to reference Kittl EM, Haberhauer G, Ruckser R et al (1997) Serum levels of soluble CD44 variant isoforms are elevated in rheumatoid arthritis. Rheumatol Int 16(5):181–186PubMedCrossRef Kittl EM, Haberhauer G, Ruckser R et al (1997) Serum levels of soluble CD44 variant isoforms are elevated in rheumatoid arthritis. Rheumatol Int 16(5):181–186PubMedCrossRef
16.
go back to reference Lesley J, Hyman R, English N et al (1997) CD44 in inflammation and metastasis. Glycoconj J 14(5):611–622PubMedCrossRef Lesley J, Hyman R, English N et al (1997) CD44 in inflammation and metastasis. Glycoconj J 14(5):611–622PubMedCrossRef
17.
go back to reference Ashida K, Terada T, Kitamura Y et al (1998) Expression of E-cadherin, α-catenin, β-catenin, and CD44 (standard and variant isoforms) in human cholangiocarcinoma: an immunohistochemical study. Hepatology 27(4):974–982PubMedCrossRef Ashida K, Terada T, Kitamura Y et al (1998) Expression of E-cadherin, α-catenin, β-catenin, and CD44 (standard and variant isoforms) in human cholangiocarcinoma: an immunohistochemical study. Hepatology 27(4):974–982PubMedCrossRef
18.
go back to reference Sato K, Murai H, Ueda Y et al (2006) Intrahepatic sarcomatoid cholangiocarcinoma of round cell variant: a case report and immunohistochemical studies. Virchows Arch 449(5):585–590PubMedCrossRef Sato K, Murai H, Ueda Y et al (2006) Intrahepatic sarcomatoid cholangiocarcinoma of round cell variant: a case report and immunohistochemical studies. Virchows Arch 449(5):585–590PubMedCrossRef
19.
go back to reference Mikami T, Saegusa M, Mitomi H et al (2001) Significant correlations of E-cadherin, catenin, and CD44 variant form expression with carcinoma cell differentiation and prognosis of extrahepatic bile duct carcinomas. Am J Clin Pathol 116(3):369–376PubMedCrossRef Mikami T, Saegusa M, Mitomi H et al (2001) Significant correlations of E-cadherin, catenin, and CD44 variant form expression with carcinoma cell differentiation and prognosis of extrahepatic bile duct carcinomas. Am J Clin Pathol 116(3):369–376PubMedCrossRef
20.
go back to reference Naor D, Wallach-Dayan SB, Zahalka MA et al (2008) Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Semin Cancer Biol 18(4):260–267PubMedCrossRef Naor D, Wallach-Dayan SB, Zahalka MA et al (2008) Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Semin Cancer Biol 18(4):260–267PubMedCrossRef
21.
go back to reference Regauer S, Ott A, Berghold A et al (1999) CD44 expression in sinonasal melanomas: is loss of isoform expression associated with advanced tumour stage? J Pathol 187(2):184–190PubMedCrossRef Regauer S, Ott A, Berghold A et al (1999) CD44 expression in sinonasal melanomas: is loss of isoform expression associated with advanced tumour stage? J Pathol 187(2):184–190PubMedCrossRef
22.
go back to reference Aaltomaa S, Lipponen P, Ala-Opas M et al (2001) Expression and prognostic value of CD44 standard and variant v3 and v6 isoforms in prostate cancer. Eur Urol 39(2):138–144PubMedCrossRef Aaltomaa S, Lipponen P, Ala-Opas M et al (2001) Expression and prognostic value of CD44 standard and variant v3 and v6 isoforms in prostate cancer. Eur Urol 39(2):138–144PubMedCrossRef
23.
go back to reference Nathan H, Pawlik TM (2010) Staging of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol 26(3):269–273PubMedCrossRef Nathan H, Pawlik TM (2010) Staging of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol 26(3):269–273PubMedCrossRef
24.
go back to reference Bourguignon LY (2008) Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin Cancer Biol 18(4):251–259PubMedCrossRef Bourguignon LY (2008) Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin Cancer Biol 18(4):251–259PubMedCrossRef
25.
go back to reference Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4(1):33–45PubMedCrossRef Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4(1):33–45PubMedCrossRef
26.
go back to reference Draffin JE, McFarlane S, Hill A et al (2004) CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res 64(16):5702–5711PubMedCrossRef Draffin JE, McFarlane S, Hill A et al (2004) CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res 64(16):5702–5711PubMedCrossRef
27.
go back to reference Afify A, Purnell P, Nguyen L (2009) Role of CD44s and CD44v6 on human breast cancer cell adhesion, migration, and invasion. Exp Mol Pathol 86(2):95–100PubMedCrossRef Afify A, Purnell P, Nguyen L (2009) Role of CD44s and CD44v6 on human breast cancer cell adhesion, migration, and invasion. Exp Mol Pathol 86(2):95–100PubMedCrossRef
28.
go back to reference Li CZ, Liu B, Wen ZQ et al (2008) Inhibition of CD44 expression by small interfering RNA to suppress the growth and metastasis of ovarian cancer cells in vitro and in vivo. Folia Biol 54(6):180–186 Li CZ, Liu B, Wen ZQ et al (2008) Inhibition of CD44 expression by small interfering RNA to suppress the growth and metastasis of ovarian cancer cells in vitro and in vivo. Folia Biol 54(6):180–186
29.
go back to reference Torre C, Wang SJ, Xia W et al (2010) Reduction of hyaluronan-CD44-mediated growth, migration, and cisplatin resistance in head and neck cancer due to inhibition of Rho kinase and PI-3 kinase signaling. Arch Otolaryngol Head Neck Surg 136(5):493–501PubMedCrossRef Torre C, Wang SJ, Xia W et al (2010) Reduction of hyaluronan-CD44-mediated growth, migration, and cisplatin resistance in head and neck cancer due to inhibition of Rho kinase and PI-3 kinase signaling. Arch Otolaryngol Head Neck Surg 136(5):493–501PubMedCrossRef
30.
go back to reference Alstergren P, Zhu B, Glogauer M et al (2004) Polarization and directed migration of murine neutrophils is dependent on cell surface expression of CD44. Cell Immunol 231(1–2):146–157PubMedCrossRef Alstergren P, Zhu B, Glogauer M et al (2004) Polarization and directed migration of murine neutrophils is dependent on cell surface expression of CD44. Cell Immunol 231(1–2):146–157PubMedCrossRef
31.
go back to reference Zhu B, Suzuki K, Goldberg HA et al (2004) Osteopontin modulates CD44-dependent chemotaxis of peritoneal macrophages through G-protein-coupled receptors: evidence of a role for an intracellular form of osteopontin. J Cell Physiol 198(1):155–167PubMedCrossRef Zhu B, Suzuki K, Goldberg HA et al (2004) Osteopontin modulates CD44-dependent chemotaxis of peritoneal macrophages through G-protein-coupled receptors: evidence of a role for an intracellular form of osteopontin. J Cell Physiol 198(1):155–167PubMedCrossRef
32.
go back to reference Suzuki K, Zhu B, Rittling SR et al (2002) Colocalization of intracellular osteopontin with CD44 is associated with migration, cell fusion, and resorption in osteoclasts. J Bone Miner Res 17(8):1486–1497PubMedCrossRef Suzuki K, Zhu B, Rittling SR et al (2002) Colocalization of intracellular osteopontin with CD44 is associated with migration, cell fusion, and resorption in osteoclasts. J Bone Miner Res 17(8):1486–1497PubMedCrossRef
33.
go back to reference Bourguignon LY, Zhu H, Zhou B et al (2001) Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth. J Biol Chem 276(52):48679–48692PubMedCrossRef Bourguignon LY, Zhu H, Zhou B et al (2001) Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth. J Biol Chem 276(52):48679–48692PubMedCrossRef
34.
go back to reference Caers J, Gunthert U, De Raeve H et al (2006) The involvement of osteopontin and its receptors in multiple myeloma cell survival, migration and invasion in the murine 5T33MM model. Br J Haematol 132(4):469–477PubMed Caers J, Gunthert U, De Raeve H et al (2006) The involvement of osteopontin and its receptors in multiple myeloma cell survival, migration and invasion in the murine 5T33MM model. Br J Haematol 132(4):469–477PubMed
35.
go back to reference Wang SJ, Wreesmann VB, Bourguignon LY (2007) Association of CD44 V3-containing isoforms with tumor cell growth, migration, matrix metalloproteinase expression, and lymph node metastasis in head and neck cancer. Head Neck 29(6):550–558PubMedCrossRef Wang SJ, Wreesmann VB, Bourguignon LY (2007) Association of CD44 V3-containing isoforms with tumor cell growth, migration, matrix metalloproteinase expression, and lymph node metastasis in head and neck cancer. Head Neck 29(6):550–558PubMedCrossRef
36.
go back to reference Weber GF, Ashkar S, Glimcher MJ et al (1996) Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science 271(5248):509–512PubMedCrossRef Weber GF, Ashkar S, Glimcher MJ et al (1996) Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science 271(5248):509–512PubMedCrossRef
37.
go back to reference Tzircotis G, Thorne RF, Isacke CM (2005) Chemotaxis towards hyaluronan is dependent on CD44 expression and modulated by cell type variation in CD44-hyaluronan binding. J Cell Sci 118(Pt 21):5119–5128PubMedCrossRef Tzircotis G, Thorne RF, Isacke CM (2005) Chemotaxis towards hyaluronan is dependent on CD44 expression and modulated by cell type variation in CD44-hyaluronan binding. J Cell Sci 118(Pt 21):5119–5128PubMedCrossRef
38.
go back to reference Yu Q, Stamenkovic I (1999) Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev 13(1):35–48PubMedCrossRef Yu Q, Stamenkovic I (1999) Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev 13(1):35–48PubMedCrossRef
39.
go back to reference Redondo-Munoz J, Ugarte-Berzal E, Garcia-Marco JA et al (2008) α4β1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells. Blood 112(1):169–178PubMedCrossRef Redondo-Munoz J, Ugarte-Berzal E, Garcia-Marco JA et al (2008) α4β1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells. Blood 112(1):169–178PubMedCrossRef
40.
go back to reference Zhang Y, Thant AA, Machida K et al (2002) Hyaluronan-CD44s signaling regulates matrix metalloproteinase-2 secretion in a human lung carcinoma cell line QG90. Cancer Res 62(14):3962–3965PubMed Zhang Y, Thant AA, Machida K et al (2002) Hyaluronan-CD44s signaling regulates matrix metalloproteinase-2 secretion in a human lung carcinoma cell line QG90. Cancer Res 62(14):3962–3965PubMed
41.
go back to reference Takahashi K, Eto H, Tanabe KK (1999) Involvement of CD44 in matrix metalloproteinase-2 regulation in human melanoma cells. Int J Cancer 80(3):387–395PubMedCrossRef Takahashi K, Eto H, Tanabe KK (1999) Involvement of CD44 in matrix metalloproteinase-2 regulation in human melanoma cells. Int J Cancer 80(3):387–395PubMedCrossRef
42.
go back to reference Samanna V, Wei H, Ego-Osuala D et al (2006) α-V-dependent outside-in signaling is required for the regulation of CD44 surface expression, MMP-2 secretion, and cell migration by osteopontin in human melanoma cells. Exp Cell Res 312(12):2214–2230PubMedCrossRef Samanna V, Wei H, Ego-Osuala D et al (2006) α-V-dependent outside-in signaling is required for the regulation of CD44 surface expression, MMP-2 secretion, and cell migration by osteopontin in human melanoma cells. Exp Cell Res 312(12):2214–2230PubMedCrossRef
43.
go back to reference Yanagisawa N, Mikami T, Mitomi H et al (2001) CD44 variant overexpression in gallbladder carcinoma associated with tumor dedifferentiation. Cancer 91(2):408–416PubMedCrossRef Yanagisawa N, Mikami T, Mitomi H et al (2001) CD44 variant overexpression in gallbladder carcinoma associated with tumor dedifferentiation. Cancer 91(2):408–416PubMedCrossRef
44.
go back to reference Sugino T, Gorham H, Yoshida K et al (1996) Progressive loss of CD44 gene expression in invasive bladder cancer. Am J Pathol 149(3):873–882PubMed Sugino T, Gorham H, Yoshida K et al (1996) Progressive loss of CD44 gene expression in invasive bladder cancer. Am J Pathol 149(3):873–882PubMed
Metadata
Title
Silencing of CD44 by siRNA suppressed invasion, migration and adhesion to matrix, but not secretion of MMPs, of cholangiocarcinoma cells
Authors
Pongsanat Pongcharoen
Artit Jinawath
Rutaiwan Tohtong
Publication date
01-12-2011
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 8/2011
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-011-9414-8

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