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

HGF/c-met/Stat3 signaling during skin tumor cell invasion: indications for a positive feedback loop

Authors: Zanobia A Syed, Weihong Yin, Kendall Hughes, Jennifer N Gill, Runhua Shi, John L Clifford

Published in: BMC Cancer | Issue 1/2011

Login to get access

Abstract

Background

Stat3 is a cytokine- and growth factor-inducible transcription factor that regulates cell motility, migration, and invasion under normal and pathological situations, making it a promising target for cancer therapeutics. The hepatocyte growth factor (HGF)/c-met receptor tyrosine kinase signaling pathway is responsible for stimulation of cell motility and invasion, and Stat3 is responsible for at least part of the c-met signal.

Methods

We have stably transfected a human squamous cell carcinoma (SCC) cell line (SRB12-p9) to force the expression of a dominant negative form of Stat3 (S3DN), which we have previously shown to suppress Stat3 activity. The in vitro and in vivo malignant behavior of the S3DN cells was compared to parental and vector transfected controls.

Results

Suppression of Stat3 activity impaired the ability of the S3DN cells to scatter upon stimulation with HGF (c-met ligand), enhanced their adhesion, and diminished their capacity to invade in vitro and in vivo. Surprisingly, S3DN cells also showed suppressed HGF-induced activation of c-met, and had nearly undetectable basal c-met activity, as revealed by a phospho-specific c-met antibody. In addition, we showed that there is a strong membrane specific localization of phospho-Stat3 in the wild type (WT) and vector transfected control (NEO4) SRB12-p9 cells, which is lost in the S3DN cells. Finally, co-immunoprecipitation experiments revealed that S3DN interfered with Stat3/c-met interaction.

Conclusion

These studies are the first confirm that interference with the HGF/c-met/Stat3 signaling pathway can block tumor cell invasion in an in vivo model. We also provide novel evidence for a possible positive feedback loop whereby Stat3 can activate c-met, and we correlate membrane localization of phospho-Stat3 with invasion in vivo.
Appendix
Available only for authorised users
Literature
1.
Ihle JN: The Stat family in cytokine signaling. Curr Opin Cell Biol. 2001, 13 (2): 211-10.1016/S0955-0674(00)00199-X.CrossRefPubMed
2.
Williams JG: STAT signalling in cell proliferation and in development. Curr Opin Genet Dev. 2000, 10 (5): 503-10.1016/S0959-437X(00)00119-2.CrossRefPubMed
3.
Bowman T, Garcia R, Turkson J, Jove R: STATs in oncogenesis. Oncogene. 2000, 19 (21): 2474-10.1038/sj.onc.1203527.CrossRefPubMed
4.
5.
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE: Stat3 as an Oncogene. Cell. 1999, 98 (3): 295-10.1016/S0092-8674(00)81959-5.CrossRefPubMed
6.
Yu H, Kortylewski M, Pardoll D: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007, 7 (1): 41-10.1038/nri1995.CrossRefPubMed
7.
Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K, Tomita K, Komiyama S, Weinstein IB: Constitutive Activation of Signal Transducers and Activators of Transcription 3 Correlates with Cyclin D1 Overexpression and May Provide a Novel Prognostic Marker in Head and Neck Squamous Cell Carcinoma. Cancer Res. 2002, 62 (12): 3351-3355.PubMed
8.
Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, Irby R, Yeatman T, Courtneidge SA, Jove R: Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci USA. 2001, 98 (13): 7319-7324. 10.1073/pnas.131568898.CrossRefPubMedPubMedCentral
9.
Zushi S, Shinomura Y, Kiyohara T, Miyazaki Y, Kondo S, Sugimachi M, Higashimoto Y, Kanayama S, Matsuzawa Y: STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells. Int J Cancer. 1998, 78 (3): 326-330. 10.1002/(SICI)1097-0215(19981029)78:3<326::AID-IJC12>3.0.CO;2-4.CrossRefPubMed
10.
Aoki Y, Feldman GM, Tosato G: Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood. 2003, 101 (4): 1535-1542. 10.1182/blood-2002-07-2130.CrossRefPubMed
11.
Bhattacharya S, Ray RM, Johnson LR: STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells. Biochem J. 2005, 392 (2): 335-344. 10.1042/BJ20050465.CrossRefPubMedPubMedCentral
12.
Dechow TN, Pedranzini L, Leitch A, Leslie K, Gerald WL, Linkov I, Bromberg JF: Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc Natl Acad Sci USA. 2004, 101 (29): 10602-10607. 10.1073/pnas.0404100101.CrossRefPubMedPubMedCentral
13.
Itoh M, Murata T, Suzuki T, Shindoh M, Nakajima K, Imai K, Yoshida K: Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells. Oncogene. 2005, 25 (8): 1195-CrossRef
14.
Xie Tx, Wei D, Liu M, Gao AC, Ali-Osman F, Sawaya R, Huang S: Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene. 2004, 23 (20): 3550-10.1038/sj.onc.1207383.CrossRefPubMed
15.
Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Shumin Z, Wang T, Sinibaldi D, Coppola D, et al: Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002, 21 (13): 2000-10.1038/sj.onc.1205260.CrossRefPubMed
16.
Hung W, Elliott B: Co-operative Effect of c-Src Tyrosine Kinase and Stat3 in Activation of Hepatocyte Growth Factor Expression in Mammary Carcinoma Cells. J Biol Chem. 2001, 276 (15): 12395-12403. 10.1074/jbc.M010715200.CrossRefPubMed
17.
Galm O, Yoshikawa H, Esteller M, Osieka R, Herman JG: SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood. 2003, 101 (7): 2784-2788. 10.1182/blood-2002-06-1735.CrossRefPubMed
18.
Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC, Herman JG: SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet. 2001, 28 (1): 29-PubMed
19.
Chan KS, Carbajal S, Kiguchi K, Clifford J, Sano S, DiGiovanni J: Epidermal Growth Factor Receptor-Mediated Activation of Stat3 during Multistage Skin Carcinogenesis. Cancer Res. 2004, 64 (7): 2382-2389. 10.1158/0008-5472.CAN-03-3197.CrossRefPubMed
20.
Zhang Y, Wang L, Jove R, Vande Woude G: Requirement of Stat3 for HGF/SF-Met mediated tumorigenesis. Oncogene. 2002, 21 (2): 217-226. 10.1038/sj.onc.1205004.CrossRefPubMed
21.
Sherry MM, Reeves A, Wu JK, Cochran BH: STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells. 2009, 27 (10): 2383-2392. 10.1002/stem.185.CrossRefPubMedPubMedCentral
22.
Darnell JE: Validating Stat3 in cancer therapy. Nat Med. 2005, 11 (6): 595-596. 10.1038/nm0605-595.CrossRefPubMed
23.
Kortylewski M, Swiderski P, Herrmann A, Wang L, Kowolik C, Kujawski M, Lee H, Scuto A, Liu Y, Yang C, et al: In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat Biotechnol. 2009, 27 (10): 925-932. 10.1038/nbt.1564.CrossRefPubMedPubMedCentral
24.
25.
Chan KS, Sano S, Kiguchi K, Anders J, Komazawa N, Takeda J, DiGiovanni J: Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Invest. 2004, 114 (5): 720-CrossRefPubMedPubMedCentral
26.
Kataoka K, Kim DJ, Carbajal S, Clifford JL, DiGiovanni J: Stage-specific disruption of Stat3 demonstrates a direct requirement during both the initiation and promotion stages of mouse skin tumorigenesis. Carcinogenesis. 2008, 29 (6): 1108-1114. 10.1093/carcin/bgn061.CrossRefPubMedPubMedCentral
27.
Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, Itami S, Nickoloff BJ, DiGiovanni J: Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med. 2005, 11 (1): 43-10.1038/nm1162.CrossRefPubMed
28.
Kim DJ, Kataoka K, Rao D, Kiguchi K, Cotsarelis G, Digiovanni J: Targeted disruption of stat3 reveals a major role for follicular stem cells in skin tumor initiation. Cancer Res. 2009, 69 (19): 7587-7594. 10.1158/0008-5472.CAN-09-1180.CrossRefPubMedPubMedCentral
29.
Kim DJ, Chan KS, Sano S, DiGiovanni J: Signal transducer and activator of transcription 3 (Stat3) in epithelial carcinogenesis. Molecular Carcinogenesis. 2007, 46 (8): 725-731. 10.1002/mc.20342.CrossRefPubMed
30.
Sano S, Chan KS, DiGiovanni J: Impact of Stat3 activation upon skin biology: A dichotomy of its role between homeostasis and diseases. J Dermatol Sci. 2008, 50 (1): 1-14. 10.1016/j.jdermsci.2007.05.016.CrossRefPubMed
31.
Suiqing C, Min Z, Lirong C: Overexpression of Phosphorylated-STAT3 Correlated with the Invasion and Metastasis of Cutaneous Squamous Cell Carcinoma. J Dermatol Sci. 2005, 32 (5): 354-360.CrossRef
32.
Clifford J, Walch E, Yang X, Xu X, Alberts D, Clayman G, El-Naggar A, Lotan R, Lippman S: Suppression of type I interferon signaling proteins is an early event in squamous skin carcinogenesis. Clin Cancer Res. 2002, 8 (7): 2067-2072.PubMed
33.
Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Nagayasu T, Sekine I: Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors. J Clin Pathol. 2005, 58 (8): 833-838. 10.1136/jcp.2004.023416.CrossRefPubMedPubMedCentral
34.
Kira M, Sano S, Takagi S, Yoshikawa K, Takeda J, Itami S: STAT3 Deficiency in Keratinocytes Leads to Compromised Cell Migration through Hyperphosphorylation of p130cas. J Biol Chem. 2002, 277 (15): 12931-12936. 10.1074/jbc.M110795200.CrossRefPubMed
35.
Gherardi E, Stoker M: Hepatocyte growth factor-scatter factor: mitogen, motogen, and met. Cancer Cells. 1991, 3 (6): 227-232.PubMed
36.
Cortner J, Vande Woode G, Rong S: The Met-HGF/SF autocrine signaling mechanism is involved in sarcomogenesis. EXS. 1995, 74: 89-121.PubMed
37.
Di Renzo MF, Olivero M, Martone T, Maffe A, Maggiora P, De Stefani A, Valente G, Giordano S, Cortesina G, Comoglio PM: Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene. 2000, 19 (12): 1547-1555. 10.1038/sj.onc.1203455.CrossRefPubMed
38.
Ma PC, Kijima T, Maulik G, Fox EA, Sattler M, Griffin JD, Johnson BE, Salgia R: c-MET Mutational Analysis in Small Cell Lung Cancer: Novel Juxtamembrane Domain Mutations Regulating Cytoskeletal Functions. Cancer Res. 2003, 63 (19): 6272-6281.PubMed
39.
Boccaccio C, Ando M, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio PM: Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature. 1998, 391 (6664): 285-288. 10.1038/34657.CrossRefPubMed
40.
Cramer A, Kleiner S, Westermann M, Meissner A, Lange A, Friedrich K: Activation of the c-Met receptor complex in fibroblasts drives invasive cell behavior by signaling through transcription factor STAT3. Journal of Cellular Biochemistry. 2005, 95 (4): 805-816. 10.1002/jcb.20459.CrossRefPubMed
41.
Cheng N, Chytil A, Shyr Y, Joly A, Moses HL: Transforming growth factor-beta signaling-deficient fibroblasts enhance hepatocyte growth factor signaling in mammary carcinoma cells to promote scattering and invasion. Mol Cancer Res. 2008, 6 (10): 1521-1533. 10.1158/1541-7786.MCR-07-2203.CrossRefPubMedPubMedCentral
42.
Wojcik EJ, Sharifpoor S, Miller NA, Wright TG, Watering R, Tremblay EA, Swan K, Mueller CR, Elliott BE: A novel activating function of c-Src and Stat3 on HGF transcription in mammary carcinoma cells. Oncogene. 2006, 25 (19): 2773-2784. 10.1038/sj.onc.1209306.CrossRefPubMed
43.
Yin W, Cheepala S, Roberts J, Syson-Chan K, DiGiovanni J, Clifford J: Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions. Molecular Cancer. 2006, 5 (1): 15-10.1186/1476-4598-5-15.CrossRefPubMedPubMedCentral
44.
Caldenhoven E, van Dijk T, Solari R, Armstrong J, Raaijmakers J, Lammers J, Koenderman L, de Groot R: STAT3beta, a Splice Variant of Transcription Factor STAT3, Is a Dominant Negative Regulator of Transcription. J Biol Chem. 1996, 271 (22): 13221-13227.PubMed
45.
Schaefer T, Sanders L, Nathans D: Cooperative transcriptional activity of Jun and Stat3 beta, a short form of Stat3. Proc Natl Acad Sci USA. 1995, 92 (20): 9097-9101. 10.1073/pnas.92.20.9097.CrossRefPubMedPubMedCentral
46.
47.
Gohda E, Kataoka H, Tsubouchi H, Daikilara Y, Yamamoto I: Phorbol ester-induced secretion of human hepatocyte growth factor by human skin fibroblasts and its inhibition by dexamethasone. FEBS Letters. 1992, 301 (1): 107-10.1016/0014-5793(92)80220-B.CrossRefPubMed
48.
Syed Z, Cheepala SB, Gill JN, Stein J, Nathan CA, DiGiovanni J, Batra V, Adegboyega P, Kleiner HE, Clifford JL: All-trans retinoic acid suppresses Stat3 signaling during skin carcinogenesis. Cancer Prevention Research. 2009, 2: 903-911. 10.1158/1940-6207.CAPR-09-0041.CrossRefPubMed
49.
Leong PL, Andrews GA, Johnson DE, Dyer KF, Xi S, Mai JC, Robbins PD, Gadiparthi S, Burke NA, Watkins SF, et al: Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci USA. 2003, 100 (7): 4138-4143. 10.1073/pnas.0534764100.CrossRefPubMedPubMedCentral
50.
Chen SY, Chen HC: Direct Interaction of Focal Adhesion Kinase (FAK) with Met Is Required for FAK To Promote Hepatocyte Growth Factor-Induced Cell Invasion. Mol Cell Biol. 2006, 26 (13): 5155-5167. 10.1128/MCB.02186-05.CrossRefPubMedPubMedCentral
51.
Silver DL, Naora H, Liu J, Cheng W, Montell DJ: Activated Signal Transducer and Activator of Transcription (STAT) 3: Localization in Focal Adhesions and Function in Ovarian Cancer Cell Motility. Cancer Res. 2004, 64 (10): 3550-3558. 10.1158/0008-5472.CAN-03-3959.CrossRefPubMed
52.
Gao SP, Bromberg JF: Touched and Moved by STAT3. Sci STKE. 2006, 2006 (343): pe30-10.1126/stke.3432006pe30.PubMed
53.
Ng DCH, Lin BH, Lim CP, Huang G, Zhang T, Poli V, Cao X: Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin. J Cell Biol. 2006, 172 (2): 245-257. 10.1083/jcb.200503021.CrossRefPubMedPubMedCentral
54.
Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE: Mitochondrial STAT3 Supports Ras-Dependent Oncogenic Transformation. Science. 2009, 324 (5935): 1713-1716. 10.1126/science.1171721.CrossRefPubMedPubMedCentral
55.
Wegrzyn J, Potla R, Chwae YJ, Sepuri NBV, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, et al: Function of Mitochondrial Stat3 in Cellular Respiration. Science. 2009, 323 (5915): 793-797. 10.1126/science.1164551.CrossRefPubMedPubMedCentral
56.
Corvinus FM, Orth C, Moriggl R, Tsareva SA, Wagner S, Pfitzner EB, Baus D, Kaufmann R, Huber LA, Zatloukal K, et al: Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia. 2005, 7 (6): 545-555. 10.1593/neo.04571.CrossRefPubMedPubMedCentral
Metadata
Title
HGF/c-met/Stat3 signaling during skin tumor cell invasion: indications for a positive feedback loop
Authors
Zanobia A Syed
Weihong Yin
Kendall Hughes
Jennifer N Gill
Runhua Shi
John L Clifford
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-180

Other articles of this Issue 1/2011

BMC Cancer 1/2011 Go to the issue

Research article

An overview of cancer/testis antigens expression in classical Hodgkin's lymphoma (cHL) identifies MAGE-A family and MAGE-C1 as the most frequently expressed antigens in a set of Brazilian cHL patients

Research article

A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis

Research article

P53 in human melanoma fails to regulate target genes associated with apoptosis and the cell cycle and may contribute to proliferation

Research article

Loss of aquaporin-4 expression and putative function in non-small cell lung cancer

Research article

Societal Costs and Benefits of Treatment with Trastuzumab in Patients with Early HER2neu-Overexpressing Breast Cancer in Singapore

Research article

Isomalto oligosaccharide sulfate inhibits tumor growth and metastasis of hepatocellular carcinoma in nude mice
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