Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cellular Oncology
Published in: Cellular Oncology 5/2017

01-10-2017 | Original Paper

Serine peptidase inhibitor Kazal type 1 (SPINK1) as novel downstream effector of the cadherin-17/β-catenin axis in hepatocellular carcinoma

Authors: Felix H. Shek, Ruibang Luo, Brian Y. H. Lam, Wing Kin Sung, Tak-Wah Lam, John M. Luk, Ming Sum Leung, Kin Tak Chan, Hector K. Wang, Chung Man Chan, Ronnie T. Poon, Nikki P. Lee

Published in: Cellular Oncology | Issue 5/2017

Login to get access

Abstract

Background

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Previously, we reported that cadherin-17 (CDH17) and its related CDH17/β-catenin axis may be responsible for inducing HCC in a subset of patients exhibiting CDH17 over-expression. Here we aimed at obtaining a better understanding of the CDH17-related HCC biology and to obtain further indications for the design of targeted therapies in CDH17 over-expressing HCC patients.

Results

We found that SPINK1 acts as a downstream effector of the CDH17/β-catenin axis in HCC. In addition, we found that SPINK1 expression exhibited a positive correlation with CDH17 expression in human HCCs and was over-expressed in up to 70% of the tumors. We identified SPINK1 as a downstream effector of the CDH17/β-catenin axis using a spectrum of in vitro assays, including gene expression modulation and inhibitor assays, bioinformatics analyses and luciferase reporter assays. These in vitro results were validated in primary human HCCs, including the observation that alteration in β-catenin expression (a core component of the CDH17/β-catenin axis) in tumors affects SPINK1 serum levels in HCC patients. Similar to CDH17, SPINK1 expression in HCC cells was found to be associated with specific tumor-related properties via activating the c-Raf/MEK/ERK pathway.

Conclusions

Our current data substantiate our knowledge on the role of CDH17 in the biology of HCC and suggest that components of the CDH17/β-catenin axis may serve as therapeutic targets in CDH17 over-expressing HCC patients.
Appendix
Available only for authorised users
Literature
1.
J. Liu, X. Wei, Y. Wu, Y. Wang, Y. Qiu, J. Shi, H. Zhou, Z. Lu, M. Shao, L. Yu, L. Tong, Giganteaside D induces ROS-mediated apoptosis in human hepatocellular carcinoma cells through the MAPK pathway. Cell. Oncol. 39, 333–342 (2016)
2.
V. Ramesh, K. Selvarasu, J. Pandian, S. Myilsamy, C. Shanmugasundaram, K. Ganesan, NFkappaB activation demarcates a subset of hepatocellular carcinoma patients for targeted therapy. Cell. Oncol. 39, 523–536 (2016)
3.
B.W. Wong, J.M. Luk, I.O. Ng, M.Y. Hu, K.D. Liu, S.T. Fan, Identification of liver-intestine cadherin in hepatocellular carcinoma--a potential disease marker. Biochem. Biophys. Res. Commun. 311, 618–624 (2003)CrossRefPubMed
4.
Z.B. Ding, Y.H. Shi, J. Zhou, G.M. Shi, A.W. Ke, S.J. Qiu, X.Y. Wang, Z. Dai, Y. Xu, J. Fan, Liver-intestine cadherin predicts microvascular invasion and poor prognosis of hepatitis B virus-positive hepatocellular carcinoma. Cancer 115, 4753–4765 (2009)CrossRefPubMed
5.
L.X. Liu, N.P. Lee, V.W. Chan, W. Xue, L. Zender, C. Zhang, M. Mao, H. Dai, X.L. Wang, M.Z. Xu, T.K. Lee, I.O. Ng, Y. Chen, H.F. Kung, S.W. Lowe, R.T. Poon, J.H. Wang, J.M. Luk, Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma. Hepatology 50, 1453–1463 (2009)CrossRefPubMedPubMedCentral
6.
M.W. Wendeler, R. Jung, H. Himmelbauer, R. Gessner, Unique gene structure and paralogy define the 7D-cadherin family. Cell Mol. Life Sci. 63, 1564–1573 (2006)CrossRefPubMed
7.
N.P. Lee, R.T. Poon, F.H. Shek, I.O. Ng, J.M. Luk, Role of cadherin-17 in oncogenesis and potential therapeutic implications in hepatocellular carcinoma. Biochim. Biophys. Acta 1806, 138–145 (2010)PubMed
8.
9.
M. Takamura, S. Yamagiwa, Y. Matsuda, T. Ichida, Y. Aoyagi, Involvement of liver-intestine cadherin in cancer progression. Med. Mol. Morphol. 46, 1–7 (2013)CrossRefPubMed
10.
Y. Wang, F.H. Shek, K.F. Wong, L.X. Liu, X.Q. Zhang, Y. Yuan, E. Khin, M.Y. Hu, J.H. Wang, R.T. Poon, W. Hong, N.P. Lee, J.M. Luk, Anti-cadherin-17 antibody modulates beta-catenin signaling and tumorigenecity of hepatocellular carcinoma. PLoS One 8, e72386 (2013)CrossRefPubMedPubMedCentral
11.
Z. Kan, H. Zheng, X. Liu, S. Li, T.D. Barber, Z. Gong, H. Gao, K. Hao, M.D. Willard, J. Xu, R. Hauptschein, P.A. Rejto, J. Fernandez, G. Wang, Q. Zhang, B. Wang, R. Chen, J. Wang, N.P. Lee, W. Zhou, Z. Lin, Z. Peng, K. Yi, S. Chen, L. Li, X. Fan, J. Yang, R. Ye, J. Ju, K. Wang, H. Estrella, S. Deng, P. Wei, M. Qiu, I.H. Wulur, J. Liu, M.E. Ehsani, C. Zhang, A. Loboda, W.K. Sung, A. Aggarwal, R.T. Poon, S.T. Fan, J. Wang, J. Hardwick, C. Reinhard, H. Dai, Y. Li, J.M. Luk, M. Mao, Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 23, 1422–1433 (2013)CrossRefPubMedPubMedCentral
12.
V. Au, F.H. Tsang, K. Man, S.T. Fan, R.T. Poon, N.P. Lee, Expression of ankyrin repeat and SOCS box containing 4 (ASB4) confers migration and invasion properties of hepatocellular carcinoma cells. Biosci. Trends 8, 101–110 (2014)CrossRefPubMed
13.
F.H. Tsang, V. Au, W.J. Lu, F.H. Shek, A.M. Liu, J.M. Luk, S.T. Fan, R.T. Poon, N.P. Lee, Prognostic marker microRNA-125b inhibits tumorigenic properties of hepatocellular carcinoma cells via suppressing tumorigenic molecule eIF5A2. Dig. Dis. Sci. 59, 2477–2487 (2014)CrossRefPubMed
14.
S. Fatima, N.P. Lee, F.H. Tsang, F.T. Kolligs, I.O. Ng, R.T. Poon, S.T. Fan, J.M. Luk, Dickkopf 4 (DKK4) acts on Wnt/b-catenin pathway via influencing b-catenin in hepatocellular carcinoma. Oncogene 31, 4233–4244 (2012)CrossRefPubMed
15.
I. Ivanovska, C. Zhang, A.M. Liu, K.F. Wong, N.P. Lee, P. Lewis, U. Philippar, D. Bansal, C. Buser, M. Scott, M. Mao, R.T. Poon, S.T. Fan, M.A. Cleary, J.M. Luk, H. Dai, Gene signatures derived from a c-MET-driven liver cancer mouse model predict survival of patients with hepatocellular carcinoma. PLoS One 6, e24582 (2011)CrossRefPubMedPubMedCentral
16.
N.P. Lee, F.H. Tsang, F.H. Shek, M. Mao, H. Dai, C. Zhang, S. Dong, X.Y. Guan, R.T. Poon, J.M. Luk, Prognostic significance and therapeutic potential of eukaryotic translation initiation factor 5A (eIF5A) in hepatocellular carcinoma. Int. J. Cancer 127, 968–976 (2010)CrossRefPubMed
17.
R. Zhu, K.F. Wong, N.P. Lee, K.F. Lee, J.M. Luk, HNF1a and CDX2 transcriptional factors bind to cadherin-17 (CDH17) gene promoter and modulate its expression in hepatocellular carcinoma. J. Cell. Biochem. 111, 618–626 (2010)CrossRefPubMed
18.
W.K. Sung, H. Zheng, S. Li, R. Chen, X. Liu, Y. Li, N.P. Lee, W.H. Lee, P.N. Ariyaratne, C. Tennakoon, F.H. Mulawadi, K.F. Wong, A.M. Liu, R.T. Poon, S.T. Fan, K.L. Chan, Z. Gong, Y. Hu, Z. Lin, G. Wang, Q. Zhang, T.D. Barber, W.C. Chou, A. Aggarwal, K. Hao, W. Zhou, C. Zhang, J. Hardwick, C. Buser, J. Xu, Z. Kan, H. Dai, M. Mao, C. Reinhard, J. Wang, J.M. Luk, Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat. Genet. 44, 765–769 (2012)CrossRefPubMed
19.
N.P. Lee, K.W. Leung, J.Y. Wo, P.C. Tam, W.S. Yeung, J.M. Luk, Blockage of testicular connexins induced apoptosis in rat seminiferous epithelium. Apoptosis 11, 1215–1229 (2006)CrossRefPubMed
20.
T. Marchbank, T.C. Freeman, R.J. Playford, Human pancreatic secretory trypsin inhibitor. Distribution, actions and possible role in mucosal integrity and repair. Digestion 59, 167–174 (1998)CrossRefPubMed
21.
P. Lara, F. Ortego, E. Gonzalez-Hidalgo, P. Castanera, P. Carbonero, I. Diaz, Adaptation of Spodoptera exigua (Lepidoptera: Noctuidae) to barley trypsin inhibitor BTI-CMe expressed in transgenic tobacco. Transgenic Res. 9, 169–178 (2000)CrossRefPubMed
22.
J.R. Lamb, C. Zhang, T. Xie, K. Wang, B. Zhang, K. Hao, E. Chudin, H.B. Fraser, J. Millstein, M. Ferguson, C. Suver, I. Ivanovska, M. Scott, U. Philippar, D. Bansal, Z. Zhang, J. Burchard, R. Smith, D. Greenawalt, M. Cleary, J. Derry, A. Loboda, J. Watters, R.T. Poon, S.T. Fan, C. Yeung, N.P. Lee, J. Guinney, C. Molony, V. Emilsson, C. Buser-Doepner, J. Zhu, S. Friend, M. Mao, P.M. Shaw, H. Dai, J.M. Luk, E.E. Schadt, Predictive genes in adjacent normal tissue are preferentially altered by sCNV during tumorigenesis in liver cancer and may rate limiting. PLoS One 6, e20090 (2011)CrossRefPubMedPubMedCentral
23.
F. van Roy, Beyond E-cadherin: roles of other cadherin superfamily members in cancer. Nat. Rev. Cancer 14, 121–134 (2014)CrossRefPubMed
24.
M. Takamura, M. Sakamoto, Y. Ino, T. Shimamura, T. Ichida, H. Asakura, S. Hirohashi, Expression of liver-intestine cadherin and its possible interaction with galectin-3 in ductal adenocarcinoma of the pancreas. Cancer Sci. 94, 425–430 (2003)CrossRefPubMed
25.
R.A. Bartolome, R. Barderas, S. Torres, M.J. Fernandez-Acenero, M. Mendes, J. Garcia-Foncillas, M. Lopez-Lucendo, J.I. Casal, Cadherin-17 interacts with a2b1 integrin to regulate cell proliferation and adhesion in colorectal cancer cells causing liver metastasis. Oncogene 33, 1658–1669 (2014)CrossRefPubMed
26.
H.B. Qiu, L.Y. Zhang, C. Ren, Z.L. Zeng, W.J. Wu, H.Y. Luo, Z.W. Zhou, R.H. Xu, Targeting CDH17 suppresses tumor progression in gastric cancer by downregulating Wnt/b-catenin signaling. PLoS One 8, e56959 (2013)CrossRefPubMedPubMedCentral
27.
B. Cieply, G. Zeng, T. Proverbs-Singh, D.A. Geller, S.P. Monga, Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene. Hepatology 49, 821–831 (2009)CrossRefPubMedPubMedCentral
28.
Y. Ishizaki, S. Ikeda, M. Fujimori, Y. Shimizu, T. Kurihara, T. Itamoto, A. Kikuchi, M. Okajima, T. Asahara, Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas. Int. J. Oncol. 24, 1077–1083 (2004)PubMed
29.
30.
M. Medl, E. Ogris, C. Peters-Engl, S. Leodolter, TATI (tumour-associated trypsin inhibitor) as a marker of ovarian cancer. Br. J. Cancer 71, 1051–1054 (1995)CrossRefPubMedPubMedCentral
31.
A. Lukkonen, S. Lintula, K. von Boguslawski, O. Carpen, B. Ljungberg, G. Landberg, U.H. Stenman, Tumor-associated trypsin inhibitor in normal and malignant renal tissue and in serum of renal-cell carcinoma patients. Int. J. Cancer 83, 486–490 (1999)CrossRefPubMed
32.
Y. Ohmachi, A. Murata, N. Matsuura, T. Yasuda, M. Monden, T. Mori, M. Ogawa, K. Matsubara, Specific expression of the pancreatic-secretory-trypsin-inhibitor (PSTI) gene in hepatocellular carcinoma. Int. J. Cancer 55, 728–734 (1993)CrossRefPubMed
33.
I. Lyytinen, M. Lempinen, A. Nordin, H. Makisalo, U.H. Stenman, H. Isoniemi, Prognostic significance of tumor-associated trypsin inhibitor (TATI) and human chorionic gonadotropin-b (hCGb) in patients with hepatocellular carcinoma. Scand. J. Gastroenterol. 48, 1066–1073 (2013)CrossRefPubMed
34.
A. Marshall, M. Lukk, C. Kutter, S. Davies, G. Alexander, D.T. Odom, Global gene expression profiling reveals SPINK1 as a potential hepatocellular carcinoma marker. PLoS One 8, e59459 (2013)CrossRefPubMedPubMedCentral
35.
Y.C. Lee, H.W. Pan, S.Y. Peng, P.L. Lai, W.S. Kuo, Y.H. Ou, H.C. Hsu, Overexpression of tumour-associated trypsin inhibitor (TATI) enhances tumour growth and is associated with portal vein invasion, early recurrence and a stage-independent prognostic factor of hepatocellular carcinoma. Eur. J. Cancer 43, 736–744 (2007)CrossRefPubMed
36.
W. Xu, H. Huang, L. Yu, L. Cao, Meta-analysis of gene expression profiles indicates genes in spliceosome pathway are up-regulated in hepatocellular carcinoma (HCC). Med. Oncol. 32, 96 (2015)CrossRefPubMed
37.
N. Ozaki, M. Ohmuraya, M. Hirota, S. Ida, J. Wang, H. Takamori, S. Higashiyama, H. Baba, K. Yamamura, Serine protease inhibitor Kazal type 1 promotes proliferation of pancreatic cancer cells through the epidermal growth factor receptor. Mol. Cancer Res. 7, 1572–1581 (2009)CrossRefPubMed
38.
C. Wang, L. Wang, B. Su, N. Lu, J. Song, X. Yang, W. Fu, W. Tan, B. Han, Serine protease inhibitor Kazal type 1 promotes epithelial-mesenchymal transition through EGFR signaling pathway in prostate cancer. Prostate 74, 689–701 (2014)CrossRefPubMed
39.
K.T. Chan, L.N. Tung, H.Y. Lam, M.Y. Choi, W. Tan, M.Y. Wong, S. Fatima, P.Y. Tam, H.K. Wang, E.S. Liu, Z.X. Bian, N.P. Lee, Survival benefit of a monoclonal antibody against cadherin-17 in an orthotopic liver tumor xenograft model. J. Appl. Life Sci. Int. 4, 1–10 (2016)CrossRef
40.
H.R. Chang, Trastuzumab-based neoadjuvant therapy in patients with HER2-positive breast cancer. Cancer 116, 2856–2867 (2010)CrossRefPubMed
41.
S. Lauro, C.E. Onesti, R. Righini, P. Marchetti, The use of bevacizumab in non-small cell lung cancer: an update. Anticancer Res. 34, 1537–1545 (2014)PubMed
42.
A.L. Cheng, Y.K. Kang, Z. Chen, C.J. Tsao, S. Qin, J.S. Kim, R. Luo, J. Feng, S. Ye, T.S. Yang, J. Xu, Y. Sun, H. Liang, J. Liu, J. Wang, W.Y. Tak, H. Pan, K. Burock, J. Zou, D. Voliotis, Z. Guan, Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10, 25–34 (2009)CrossRefPubMed
43.
J.M. Llovet, S. Ricci, V. Mazzaferro, P. Hilgard, E. Gane, J.F. Blanc, A.C. de Oliveira, A. Santoro, J.L. Raoul, A. Forner, M. Schwartz, C. Porta, S. Zeuzem, L. Bolondi, T.F. Greten, P.R. Galle, J.F. Seitz, I. Borbath, D. Haussinger, T. Giannaris, M. Shan, M. Moscovici, D. Voliotis, J. Bruix, Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008)CrossRefPubMed
44.
R.S. Finn, R.T. Poon, T. Yau, H.J. Klumpen, L.T. Chen, Y.K. Kang, T.Y. Kim, C. Gomez-Martin, C. Rodriguez-Lope, T. Kunz, T. Paquet, U. Brandt, D. Sellami, J. Bruix, Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma. J. Hepatol. 59, 1271–1277 (2013)CrossRefPubMed
45.
B. Ateeq, S.A. Tomlins, B. Laxman, I.A. Asangani, Q. Cao, X. Cao, Y. Li, X. Wang, F.Y. Feng, K.J. Pienta, S. Varambally, A.M. Chinnaiyan, Therapeutic targeting of SPINK1-positive prostate cancer. Sci. Transl. Med. 3, 72ra17 (2011)CrossRefPubMedPubMedCentral
46.
T. Marchbank, A. Mahmood, R.J. Playford, Pancreatic secretory trypsin inhibitor causes autocrine-mediated migration and invasion in bladder cancer and phosphorylates the EGF receptor, Akt2 and Akt3, and ERK1 and ERK2. Am. J. Physiol. Renal. Physiol. 305, F382–F389 (2013)CrossRefPubMed
Metadata
Title
Serine peptidase inhibitor Kazal type 1 (SPINK1) as novel downstream effector of the cadherin-17/β-catenin axis in hepatocellular carcinoma
Authors
Felix H. Shek
Ruibang Luo
Brian Y. H. Lam
Wing Kin Sung
Tak-Wah Lam
John M. Luk
Ming Sum Leung
Kin Tak Chan
Hector K. Wang
Chung Man Chan
Ronnie T. Poon
Nikki P. Lee
Publication date
01-10-2017
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 5/2017
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-017-0332-x

Other articles of this Issue 5/2017

Cellular Oncology 5/2017 Go to the issue

Original Paper

Crosstalk between M2 macrophages and glioma stem cells

Review

Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options

Original Paper

EphA3 targeting reduces in vitro adhesion and invasion and in vivo growth and angiogenesis of multiple myeloma cells

Report

Changes in plasma miR-9, miR-16, miR-205 and miR-486 levels after non-small cell lung cancer resection

Original Paper

Suppression of a cancer stem-like phenotype mediated by alpha-lipoic acid in human lung cancer cells through down-regulation of β-catenin and Oct-4

Original Paper

MicroRNA-100 shuttled by mesenchymal stem cell-derived exosomes suppresses in vitro angiogenesis through modulating the mTOR/HIF-1α/VEGF signaling axis in breast cancer cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits