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

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2011

Open Access 01-12-2011 | Research article

Genes Associated With Prognosis After Surgery For Malignant Pleural Mesothelioma Promote Tumor Cell Survival In Vitro

Authors: Gavin J Gordon, Raphael Bueno, David J Sugarbaker

Published in: BMC Cancer | Issue 1/2011

Login to get access

Abstract

Background

Mesothelioma is an aggressive neoplasm with few effective treatments, one being cytoreductive surgery. We previously described a test, based on differential expression levels of four genes, to predict clinical outcome in prospectively consented mesothelioma patients after surgery. In this study, we determined whether any of these four genes could be linked to a cancer relevant phenotype.

Methods

We conducted a high-throughput RNA inhibition screen to knockdown gene expression levels of the four genes comprising the test (ARHGDIA, COBLL1, PKM2, TM4SF1) in both a human lung-derived normal and a tumor cell line using three different small inhibitory RNA molecules per gene. Successful knockdown was confirmed using quantitative RT-PCR. Detection of statistically significant changes in apoptosis and mitosis was performed using immunological assays and quantified using video-assisted microscopy at a single time-point. Changes in nuclear shape, size, and numbers were used to provide additional support of initial findings. Each experiment was conducted in triplicate. Specificity was assured by requiring that at least 2 different siRNAs produced the observed change in each cell line/time-point/gene/assay combination.

Results

Knockdown of ARHGDIA, COBLL1, and TM4SF1 resulted in 2- to 4-fold increased levels of apoptosis in normal cells (ARHGDIA only) and tumor cells (all three genes). No statistically significant changes were observed in apoptosis after knockdown of PKM2 or for mitosis after knockdown of any gene.

Conclusions

We provide evidence that ARHGDIA, COBLL1, and TM4SF1 are negative regulators of apoptosis in cultured tumor cells. These genes, and their related intracellular signaling pathways, may represent potential therapeutic targets in mesothelioma.
Appendix
Available only for authorised users
Literature
1.
2.
Murayama Y, Miyagawa J, Shinomura Y, Kanayama S, Isozaki K, Yamamori K, Mizuno H, Ishiguro S, Kiyohara T, Miyazaki Y, et al: Significance of the association between heparin-binding epidermal growth factor-like growth factor and CD9 in human gastric cancer. Int J Cancer. 2002, 98 (4): 505-513. 10.1002/ijc.10198.CrossRefPubMed
3.
Lin RT, Takahashi K, Karjalainen A, Hoshuyama T, Wilson D, Kameda T, Chan CC, Wen CP, Furuya S, Higashi T, et al: Ecological association between asbestos-related diseases and historical asbestos consumption: an international analysis. Lancet. 2007, 369 (9564): 844-849. 10.1016/S0140-6736(07)60412-7.CrossRefPubMed
4.
Aisner J: Diagnosis, staging, and natural history of pleural mesothelioma. Comprehensive Textbook of Thoracic Oncology. Edited by: Aisner J, AR, Green MR, Martini N, Perry MC. 1996, Baltimore: Williams and Wilkins, 799-785.
5.
Bignon J, Brochard P, Pairon JC: Mesothelioma: causes and fiber-related mechanisms. Comprehensive Textbook of Thoracic Oncology. Edited by: AisneR J, Arriagada R, Green M, Martini N, Perry M. 1996, Baltimore: Williams and Wilkins, 735-756.
6.
Boutin C, Schlesser M, Frenay C, Astoul P: Malignant pleural mesothelioma. Eur Respir J. 1998, 12 (4): 972-981. 10.1183/09031936.98.12040972.CrossRefPubMed
7.
Corson JM, Renshaw AA: Pathology of mesothelioma. Comprehensive Textbook of Thoracic Oncology. Edited by: AisneR J, Arriagada R, Green MR, Martini N, Perry MC. 1996, Baltimore: Williams and Wilkins, 757-758.
8.
Kindler HL, Vogelzang NJ: Mesothelioma. Oncologic Therapies. Edited by: Vokes EE, Golomb HM. 1999, Berlin: Springer-Verlag, 635-651.CrossRef
9.
Cury PM, Butcher DN, Corrin B, Nicholson AG: The use of histological and immunohistochemical markers to distinguish pleural malignant mesothelioma and in situ mesothelioma from reactive mesothelial hyperplasia and reactive pleural fibrosis. J Pathol. 1999, 189 (2): 251-257. 10.1002/(SICI)1096-9896(199910)189:2<251::AID-PATH412>3.0.CO;2-F.CrossRefPubMed
10.
Sugarbaker DJ, Norberto JJ, Bueno R: Current Therapy for Mesothelioma. Cancer Control. 1997, 4 (4): 326-334.PubMed
11.
Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, et al: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003, 21 (14): 2636-2644. 10.1200/JCO.2003.11.136.CrossRefPubMed
12.
Krug LM: An overview of chemotherapy for mesothelioma. Hematol Oncol Clin North Am. 2005, 19 (6): 1117-1136. 10.1016/j.hoc.2005.09.010. viiCrossRefPubMed
13.
Sugarbaker DJ, Norberto JJ, Swanson SJ: Extrapleural pneumonectomy in the setting of multimodality therapy for diffuse malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg. 1997, 9 (4): 373-382.PubMed
14.
Baldini EH, Recht A, Strauss GM, DeCamp MM, Swanson SJ, Liptay MJ, Mentzer SJ, Sugarbaker DJ: Patterns of failure after trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg. 1997, 63 (2): 334-338. 10.1016/S0003-4975(96)01228-3.CrossRefPubMed
15.
Flores RM: Induction chemotherapy, extrapleural pneumonectomy, and radiotherapy in the treatment of malignant pleural mesothelioma: the Memorial Sloan-Kettering experience. Lung Cancer. 2005, 49 (Suppl 1): S71-74.CrossRefPubMed
16.
Flores RM, Routledge T, Seshan VE, Dycoco J, Zakowski M, Hirth Y, Rusch VW: The impact of lymph node station on survival in 348 patients with surgically resected malignant pleural mesothelioma: implications for revision of the American Joint Committee on Cancer staging system. J Thorac Cardiovasc Surg. 2008, 136 (3): 605-610. 10.1016/j.jtcvs.2008.02.069.CrossRefPubMed
17.
Richards WG, Zellos L, Bueno R, Jaklitsch MT, Janne PA, Chirieac LR, Yeap BY, Dekkers RJ, Hartigan PM, Capalbo L, et al: Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma. J Clin Oncol. 2006, 24 (10): 1561-1567. 10.1200/JCO.2005.04.6813.CrossRefPubMed
18.
Tilleman TR, Richards WG, Zellos L, Johnson BE, Jaklitsch MT, Mueller J, Yeap BY, Mujoomdar AA, Ducko CT, Bueno R, et al: Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study. J Thorac Cardiovasc Surg. 2009, 138 (2): 405-411. 10.1016/j.jtcvs.2009.02.046.CrossRefPubMed
19.
Zellos L, Richards WG, Capalbo L, Jaklitsch MT, Chirieac LR, Johnson BE, Bueno R, Sugarbaker DJ: A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic cisplatin with amifostine cytoprotection for malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2009, 137 (2): 453-458. 10.1016/j.jtcvs.2008.07.055.CrossRefPubMed
20.
Gordon GJ, Jensen RV, Hsiao LL, Gullans SR, Blumenstock JE, Richards WG, Jaklitsch MT, Sugarbaker DJ, Bueno R: Using gene expression ratios to predict outcome among patients with mesothelioma. J Natl Cancer Inst. 2003, 95 (8): 598-605. 10.1093/jnci/95.8.598.CrossRefPubMed
21.
Gordon GJ, Rockwell GN, Godfrey PA, Jensen RV, Glickman JN, Yeap BY, Richards WG, Sugarbaker DJ, Bueno R: Validation of genomics-based prognostic tests in malignant pleural mesothelioma. Clin Cancer Res. 2005, 11 (12): 4406-4414. 10.1158/1078-0432.CCR-04-2181.CrossRefPubMedPubMedCentral
22.
Gordon GJ, Dong L, Yeap BY, Richards WG, Glickman JN, Edenfield H, Mani M, Colquitt R, Maulik G, Van Oss B, et al: Four-gene expression ratio test for survival in patients undergoing surgery for mesothelioma. J Natl Cancer Inst. 2009, 101 (9): 678-686. 10.1093/jnci/djp061.CrossRefPubMedPubMedCentral
23.
Carpenter AE, Sabatini DM: Systematic genome-wide screens of gene function. Nat Rev Genet. 2004, 5 (1): 11-22.CrossRefPubMed
24.
Echeverri CJ, Perrimon N: High-throughput RNAi screening in cultured cells: a user's guide. Nat Rev Genet. 2006, 7 (5): 373-384.CrossRefPubMed
25.
Sachse C, Weiss-Haljiti C, Holz C, Regener K, Halley F, al e: Exploring the full power of combining high throughput RNAi with high content readouts: from target discovery screens to drug modifier studies. High Content Screening: Science, Techniques and Applications. Edited by: SA H. 2008, Hoboken: John Wiley & Sons, 145-168.CrossRef
26.
Echeverri CJ, Beachy PA, Baum B, Boutros M, Buchholz F, Chanda SK, Downward J, Ellenberg J, Fraser AG, Hacohen N, et al: Minimizing the risk of reporting false positives in large-scale RNAi screens. Nat Methods. 2006, 3 (10): 777-779. 10.1038/nmeth1006-777.CrossRefPubMed
27.
Broers JL, Bronnenberg NM, Kuijpers HJ, Schutte B, Hutchison CJ, Ramaekers FC: Partial cleavage of A-type lamins concurs with their total disintegration from the nuclear lamina during apoptosis. Eur J Cell Biol. 2002, 81 (12): 677-691. 10.1078/0171-9335-00282.CrossRefPubMed
28.
Oriuchi N, Higuchi T, Hanaoka H, Iida Y, Endo K: Current status of cancer therapy with radiolabeled monoclonal antibody. Ann Nucl Med. 2005, 19 (5): 355-365. 10.1007/BF03027399.CrossRefPubMed
29.
Kao YR, Shih JY, Wen WC, Ko YP, Chen BM, Chan YL, Chu YW, Yang PC, Wu CW, Roffler SR: Tumor-associated antigen L6 and the invasion of human lung cancer cells. Clin Cancer Res. 2003, 9 (7): 2807-2816.PubMed
30.
Shih SC, Zukauskas A, Li D, Liu G, Ang LH, Nagy JA, Brown LF, Dvorak HF: The L6 protein TM4SF1 is critical for endothelial cell function and tumor angiogenesis. Cancer Res. 2009, 69 (8): 3272-3277. 10.1158/0008-5472.CAN-08-4886.CrossRefPubMedPubMedCentral
31.
Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O: Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 1999, 6 (1): 63-70. 10.1093/dnares/6.1.63.CrossRefPubMed
32.
Carroll EA, Gerrelli D, Gasca S, Berg E, Beier DR, Copp AJ, Klingensmith J: Cordon-bleu is a conserved gene involved in neural tube formation. Dev Biol. 2003, 262 (1): 16-31. 10.1016/S0012-1606(03)00323-3.CrossRefPubMed
33.
Leffers H, Nielsen MS, Andersen AH, Honore B, Madsen P, Vandekerckhove J, Celis JE: Identification of two human Rho GDP dissociation inhibitor proteins whose overexpression leads to disruption of the actin cytoskeleton. Exp Cell Res. 1993, 209 (2): 165-174. 10.1006/excr.1993.1298.CrossRefPubMed
34.
Turner SJ, Zhuang S, Zhang T, Boss GR, Pilz RB: Effects of lovastatin on Rho isoform expression, activity, and association with guanine nucleotide dissociation inhibitors. Biochem Pharmacol. 2008, 75 (2): 405-413. 10.1016/j.bcp.2007.08.031.CrossRefPubMed
35.
El Marzouk S, Schultz-Norton JR, Likhite VS, McLeod IX, Yates JR, Nardulli AM: Rho GDP dissociation inhibitor alpha interacts with estrogen receptor alpha and influences estrogen responsiveness. J Mol Endocrinol. 2007, 39 (4): 249-259. 10.1677/JME-07-0055.CrossRefPubMed
36.
Su LF, Knoblauch R, Garabedian MJ: Rho GTPases as modulators of the estrogen receptor transcriptional response. J Biol Chem. 2001, 276 (5): 3231-3237. 10.1074/jbc.M005547200.CrossRefPubMed
37.
Zhao L, Wang H, Li J, Liu Y, Ding Y: Overexpression of Rho GDP-dissociation inhibitor alpha is associated with tumor progression and poor prognosis of colorectal cancer. J Proteome Res. 2008, 7 (9): 3994-4003. 10.1021/pr800271b.CrossRefPubMed
38.
Atsushi T, Jun M, Hiroyoshi I, Miki T, Ayumi T, al e: Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDI alpha. Oncogene. 1999, 18 (39): 5373-5380. 10.1038/sj.onc.1202921.CrossRef
39.
Park YJ, Ahn HJ, Chang HK, Kim JY, Huh KH, Kim MS, Kim YS: The RhoGDI-alpha/JNK signaling pathway plays a significant role in mycophenolic acid-induced apoptosis in an insulin-secreting cell line. Cell Signal. 2009, 21 (2): 356-364. 10.1016/j.cellsig.2008.11.009.CrossRefPubMed
40.
Vander Heiden MG, Christofk HR, Schuman E, Subtelny AO, Sharfi H, Harlow EE, Xian J, Cantley LC: Identification of small molecule inhibitors of pyruvate kinase M2. Biochem Pharmacol. 2010, 79 (8): 1118-1124. 10.1016/j.bcp.2009.12.003.CrossRefPubMed
41.
Mazurek S, Boschek CB, Hugo F, Eigenbrodt E: Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol. 2005, 15 (4): 300-308. 10.1016/j.semcancer.2005.04.009.CrossRefPubMed
42.
Cao X, Littlejohn J, Rodarte C, Zhang L, Martino B, Rascoe P, Hamid K, Jupiter D, Smythe WR: Up-regulation of Bcl-xl by hepatocyte growth factor in human mesothelioma cells involves ETS transcription factors. Am J Pathol. 2009, 175 (5): 2207-2216. 10.2353/ajpath.2009.090070.CrossRefPubMedPubMedCentral
43.
Fennell DA, Rudd RM: Defective core-apoptosis signalling in diffuse malignant pleural mesothelioma: opportunities for effective drug development. Lancet Oncol. 2004, 5 (6): 354-362. 10.1016/S1470-2045(04)01492-5.CrossRefPubMed
Metadata
Title
Genes Associated With Prognosis After Surgery For Malignant Pleural Mesothelioma Promote Tumor Cell Survival In Vitro
Authors
Gavin J Gordon
Raphael Bueno
David J Sugarbaker
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-169

Other articles of this Issue 1/2011

BMC Cancer 1/2011 Go to the issue

Research article

Small interfering RNA targeting mcl-1 enhances proteasome inhibitor-induced apoptosis in various solid malignant tumors

Research article

Prognostic significance of a systemic inflammatory response in patients receiving first-line palliative chemotherapy for recurred or metastatic gastric cancer

Research article

E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion

Study protocol

INSPIRE: A phase III study of the BLP25 liposome vaccine (L-BLP25) in Asian patients with unresectable stage III non-small cell lung cancer

Research article

Association between chronic viral hepatitis infection and breast cancer risk: a nationwide population-based case-control study

Research article

Survival advantages conferred to colon cancer cells by E-selectin-induced activation of the PI3K-NFκB survival axis downstream of Death receptor-3
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