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
Tumor Biology
Published in: Tumor Biology 8/2016

01-08-2016 | Original Article

The SMAD2/3 pathway is involved in hepaCAM-induced apoptosis by inhibiting the nuclear translocation of SMAD2/3 in bladder cancer cells

Authors: Xiaorong Wang, E. Chen, Min Tang, Xue Yang, Yin Wang, Zhan Quan, Xiaohou Wu, Chunli Luo

Published in: Tumor Biology | Issue 8/2016

Login to get access

Abstract

The aim of this study was to explore the correlation between hepatocyte cell adhesion molecule (hepaCAM) and SMAD family member 2/3 (SMAD2/3) in bladder carcinoma, and the involvement of the SMAD2/3 pathway in hepaCAM-induced tumor apoptosis. Immunohistochemistry was used to measure hepaCAM and p-SMAD2/3 protein levels in bladder cancer tissues. Flow cytometry and Hoechst staining were used to study the effect of hepaCAM on cellular apoptosis. Western blot was employed to determine the expression of hepaCAM and SMAD2/3/caspase pathway molecules using a hepaCAM overexpression adenovirus, a caspase inhibitor (Z-VAD-FMK), and a SMAD2/3 activator (transforming growth factor (TGF)-β1), respectively. Translocation of p-SMAD2/3 was measured by immunofluorescence and western blot. HepaCAM proteins were significantly decreased (P < 0.05), while p-SMAD2/3 proteins were remarkably increased (P < 0.05) in bladder carcinoma compared to adjacent tissues. However, the low hepaCAM and high p-SMAD2/3 were not statistically associated with clinicopathological characteristics of the patients. A negative linear correlation between hepaCAM and p-SMAD2/3 was observed according to Pearson analysis (r = −0.712/−0.724, P = 0.008/0.011). Overexpression of hepaCAM activated caspase 3/8/9 and downregulated poly-ADP ribose polymerase (PARP) and p-SMAD2/3. Treatment of bladder cancer cells with Z-VAD-FMK + hepaCAM significantly downregulated procaspase 3/8/9 and PARP and induced cellular apoptosis, compared with that using Z-VAD-FMK alone. Similarly, combined treatment of TGF-β1 + hepaCAM significantly downregulated p-SMAD2/3, procaspase 3/8/9, and PARP and induced apoptosis of bladder cancer cells, compared with TGF-β1 alone. Overexpression of hepaCAM prevented the p-SMAD2/3 translocation from the cytoplasm to the nucleus in bladder cancer cells BIU-87 and T24. Our findings uncover that the p-SMAD2/3 pathway is critical for hepaCAM-induced cancer cell apoptosis and provide valuable insights for current and future Ad-hepaCAM and p-SMAD2/3 clinical trials.
Literature
1.
2.
Babjuk M, Burger M, Zigeuner R. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol. 2013;64:639–53.CrossRefPubMed
3.
4.
Parekh DJ, Bochner BH, Dalbagni G. Superficial and muscle-invasive bladder cancer: principles of management for outcomes assessments. J Clin Oncol. 2006;24:5519–27.CrossRefPubMed
5.
Malkowicz SB, van Poppel H, Mickisch G. Muscle-invasive urothelial carcinoma of the bladder. Urology. 2007;69:3–16.CrossRefPubMed
6.
Chung MM, Hoon LL, Shen S. Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma. J Hepatol. 2005;42:833–41.CrossRef
7.
Zhang QL, Luo CL, Wu XH. HepaCAM induces G1 phase arrest and promotes cMyc degradation in human renal cell carcinoma. J Cell Biochem. 2011;112:2910–9.CrossRefPubMed
8.
9.
Moh MC, Zhang T, Lee LH. Expression of hepaCAM is downregulated in cancers and induces senescence-like growth arrest via a p53/p21-dependent pathway in human breast cancer cells. Carcinogenesis. 2008;29:2298–305.CrossRefPubMed
10.
Tao J, Liu Q, Wu XH. Identification of hypermethylation in hepatocyte cell adhesion molecule gene promoter region in bladder carcinoma. Int J Med Sci. 2013;10:1860–7.CrossRefPubMedPubMedCentral
11.
Xu B, He YF, Wu XH. Exploration of the correlations between interferon-gamma in patient serum and HEPACAM in bladder transitional cell carcinoma, and the interferon-gamma mechanism inhibiting BIU-87 proliferation. J Urol. 2012;188:1346–53.CrossRefPubMed
12.
Zhang QL, Luo CL, Yan L. HEPACAM induces apoptosis in renal cell carcinoma 786-0 cell line. Basic Clin Med. 2011;31:73–7.
13.
Vermeulen K, Van Bockstaele DR, Berneman ZN. Apoptosis: mechanisms and relevance in cancer. Ann Hematol. 2005;84:627–39.CrossRefPubMed
14.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2005;144:646–74.CrossRef
15.
Kehmeier E, Ruhl H, Voland B. Cellular steady-state levels of “high risk” but not “low risk” human papillomavirus (HPV) E6 proteins are increased by inhibition of proteasome-dependent degradation independent of their p53- and E6AP-binding capabilities. Virology. 2011;299:72–87.CrossRef
16.
Liu Y, Zhang SP, Cai YQ. Cytoprotective effects of selenium on cadmium-induced LLC-PK1 cells apoptosis by activating JNK pathway. Toxicol. 2007;21:677–84.
17.
Mertens‐Talcott SU, Noratto GD, Li X. Betulinic acid decreases ER-negative breast cancer cell growth in vitro and in vivo: role of Sp transcription factors and microRNA-27a: ZBTB10. Mol Carcinog. 2013;52:591–602.CrossRefPubMed
18.
Feng XH, Derynck R. Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005;21:659–93.CrossRefPubMed
19.
Jones RL, Stoikos C, Findlay JK. TGF-beta superfamily expression and actions in the endometrium and placenta. Reproduction. 2006;132:217–32.CrossRefPubMed
20.
21.
Geng J, Fan J, Ouyang Q. Loss of PPM1A expression enhances invasion and the epithelial-to-mesenchymal transition in bladder cancer by activating the TGF-β/Smad signaling pathway. Oncotarget. 2014;5:5700–11.CrossRefPubMedPubMedCentral
22.
23.
Akhurst RJ, Derynck R. TGF-beta signaling in cancer-a double-edged sword. Trends Cell Biol. 2001;11:S44–51.PubMed
24.
Wakefeld LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev. 2002;12:22–9.CrossRef
25.
Mansouri-Attia N, Tripurani SK, Gokul N. TGFβ signaling promotes juvenile granulosa cell tumorigenesis by suppressing apoptosis. Mol Endocrinol. 2014;28:1887–98.CrossRefPubMedPubMedCentral
26.
Wei H, Kamat AM, Aldousari S. Genetic variations in the transforming growth factor beta pathway as predictors of bladder cancer risk. PLoS ONE. 2012;7:e51758.CrossRefPubMedPubMedCentral
27.
28.
Wilkinson DS, Ogden SK, Stratton SA, Piechan JL, Nguyen TT, Smulian GA, et al. A direct intersection between p53 and transforming growth factor beta pathways targets chromatin modification and transcription repression of the alpha-fetoprotein gene. Mol Cell Biol. 2005;25:1200–12.CrossRefPubMedPubMedCentral
29.
Du HF, Ou LP, Yang X. A new PKCα/β/TBX3/E-cadherin pathway is involved in PLCε-regulated invasion and migration in human bladder cancer cells. Cell Signal. 2014;26:580–93.CrossRefPubMed
30.
Zhao DD, Lin F, Wu XD. Pseudolaric acid B induces apoptosis via proteasome-mediated Bcl-2 degradation in hormone-refractory prostate cancer DU145 cells. Toxicol in Vitro. 2012;26:595–602.CrossRefPubMed
31.
Wang QJ, Luo CL, Wu XH. HepaCAM and p-mTOR are closely correlated in transitional cell carcinoma of bladder and expression of hepaCAM inhibits proliferation via an AMPK/mTOR-dependent pathway in human bladder cancer cells. J Urol. 2013;190:1912–8.CrossRefPubMed
32.
Xun CH, Luo CL, Wu XH. Expression of hepaCAM and its effect on proliferation of tumor cells in renal cell carcinoma. Urology. 2010;75:828–34.CrossRefPubMed
33.
Song XD, Wang Y, Du HF. Overexpression of HepaCAM inhibits cell viability and motility through suppressing nucleus translocation of androgen receptor and ERK signaling in prostate cancer. Prostate. 2014;74:1023–33.CrossRefPubMed
34.
35.
Ruchaud S, Korfali N, Villa P. Caspase-6 gene disruption reveals a requirement for lamin A cleavage in apoptotic chromatin condensation. EMBO J. 2002;21:1967–77.CrossRefPubMedPubMedCentral
36.
37.
Boulares AH, Zoltoski AJ, Contreras FJ. Regulation of DNAS1L3 endonuclease activity by poly(ADP-ribosyl)ation during etoposide-induced apoptosis. Role of poly(ADP-ribose) polymerase-1 cleavage in endonuclease activation. J Bio Chem. 2002;277:372–8.CrossRef
38.
Wang XR, Yang X, Wang Y. Inducing apoptosis of bladder cancer cell T24 by 5-azacytidine combined with adenovirus-hepaCAM via inhibiting p-AKT. J Chongqing Med Univ. 2014;39:762–7.
39.
Pierreux CE, Nicolas FJ, Hill CS. Transforming growth factor beta-independent shuttling of Smad4 between the cytoplasm and nucleus. Mol Cell Biol. 2000;20:9041–54.CrossRefPubMedPubMedCentral
40.
Xu G, Zhong Y, Munir S. Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. J Clin Endocrinol Metab. 2004;89:5523–34.CrossRefPubMed
41.
Young C, Dae KK, Jashil H. TCEA3 binds to TGF-beta receptor I and induces Smad-independent, JNK-dependent apoptosis in ovarian cancer cells. Cell Signal. 2013;25:1245–51.CrossRef
42.
Mu XX, Lin S, Yang JH. TGF-b signaling is often attenuated during hepatotumorigenesis, but is retained for the malignancy of hepatocellular carcinoma cells. PLoS ONE. 2013;8:e63436.CrossRefPubMedPubMedCentral
Metadata
Title
The SMAD2/3 pathway is involved in hepaCAM-induced apoptosis by inhibiting the nuclear translocation of SMAD2/3 in bladder cancer cells
Authors
Xiaorong Wang
E. Chen
Min Tang
Xue Yang
Yin Wang
Zhan Quan
Xiaohou Wu
Chunli Luo
Publication date
01-08-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 8/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-016-4821-8

Other articles of this Issue 8/2016

Tumor Biology 8/2016 Go to the issue

Original Article

Blockage of glutaminolysis enhances the sensitivity of ovarian cancer cells to PI3K/mTOR inhibition involvement of STAT3 signaling

Original Article

DNA methylation and histone acetylation regulate the expression of MGMT and chemosensitivity to temozolomide in malignant melanoma cell lines

Original Article

Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model

Original Article

CIZ1 interacts with YAP and activates its transcriptional activity in hepatocellular carcinoma cells

Original Article

Differential expression of PDGFRB and EGFR in microvascular proliferation in glioblastoma

Original Article

Plexin-B1 indirectly affects glioma invasiveness and angiogenesis by regulating the RhoA/αvβ3 signaling pathway and SRPK1
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