STAT3 can serve as a hit in the process of malignant transformation of primary cells

M. Demaria, S. Misale, C. Giorgi, V. Miano, A. Camporeale, J. Campisi, P. Pinton, V. Poli

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The transcription factor signal transducer and activator of transcription 3 (STAT3) acts downstream of many pro-oncogenic signals, including cytokines, growth factors and oncogenes, and is accordingly constitutively active in a wide variety of tumors that often become addicted to it. Moreover, STAT3 is a key player in mediating inflammation-driven tumorigenesis, where its aberrant continuous activation is typically triggered by local or systemic production of the pro-inflammatory cytokine IL-6. We recently showed that mouse embryonic fibroblasts (MEFs) derived from STAT3C k/in mice, which express physiological levels of the constitutively active mutant STAT3C, display features of transformed cells such as increased proliferation, resistance to apoptosis and senescence, and aerobic glycolysis. Here, we show that pre-existing constitutively active STAT3 is sufficient to prime primary MEFs for malignant transformation upon spontaneous immortalization. Transformation is strictly STAT3-dependent and correlates with high resistance to apoptosis and enhanced expression of anti-apoptotic/pro-survival genes. Additionally, hypoxia inducible factor (HIF)-1α level is elevated by twofold and contributes to STAT3 oncogenic activity by supporting high rates of aerobic glycolysis. Thus, constitutively active STAT3, an accepted essential factor for tumor growth/progression, can also act as a first hit in multistep carcinogenesis; this ability to predispose cells to malignant transformation may be particularly relevant in the pro-oncogenic niche represented by chronically inflamed tissues.

Original languageEnglish
Pages (from-to)1390-1397
Number of pages8
JournalCell Death and Differentiation
Volume19
Issue number8
DOIs
Publication statusPublished - Aug 2012

Fingerprint

STAT3 Transcription Factor
Glycolysis
Intercellular Signaling Peptides and Proteins
Carcinogenesis
Fibroblasts
Apoptosis
Cytokines
Hypoxia-Inducible Factor 1
Oncogenes
Interleukin-6
Neoplasms
Transcription Factors
Inflammation
Genes

Keywords

  • 3T3 MEFs
  • aerobic glycolysis
  • apoptosis
  • HIF-1α
  • STAT3
  • tumorigenesis

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Demaria, M., Misale, S., Giorgi, C., Miano, V., Camporeale, A., Campisi, J., ... Poli, V. (2012). STAT3 can serve as a hit in the process of malignant transformation of primary cells. Cell Death and Differentiation, 19(8), 1390-1397. https://doi.org/10.1038/cdd.2012.20

STAT3 can serve as a hit in the process of malignant transformation of primary cells. / Demaria, M.; Misale, S.; Giorgi, C.; Miano, V.; Camporeale, A.; Campisi, J.; Pinton, P.; Poli, V.

In: Cell Death and Differentiation, Vol. 19, No. 8, 08.2012, p. 1390-1397.

Research output: Contribution to journalArticle

Demaria, M, Misale, S, Giorgi, C, Miano, V, Camporeale, A, Campisi, J, Pinton, P & Poli, V 2012, 'STAT3 can serve as a hit in the process of malignant transformation of primary cells', Cell Death and Differentiation, vol. 19, no. 8, pp. 1390-1397. https://doi.org/10.1038/cdd.2012.20
Demaria M, Misale S, Giorgi C, Miano V, Camporeale A, Campisi J et al. STAT3 can serve as a hit in the process of malignant transformation of primary cells. Cell Death and Differentiation. 2012 Aug;19(8):1390-1397. https://doi.org/10.1038/cdd.2012.20
Demaria, M. ; Misale, S. ; Giorgi, C. ; Miano, V. ; Camporeale, A. ; Campisi, J. ; Pinton, P. ; Poli, V. / STAT3 can serve as a hit in the process of malignant transformation of primary cells. In: Cell Death and Differentiation. 2012 ; Vol. 19, No. 8. pp. 1390-1397.
@article{20f09a9ff553477bafd6ad7851aaf7ae,
title = "STAT3 can serve as a hit in the process of malignant transformation of primary cells",
abstract = "The transcription factor signal transducer and activator of transcription 3 (STAT3) acts downstream of many pro-oncogenic signals, including cytokines, growth factors and oncogenes, and is accordingly constitutively active in a wide variety of tumors that often become addicted to it. Moreover, STAT3 is a key player in mediating inflammation-driven tumorigenesis, where its aberrant continuous activation is typically triggered by local or systemic production of the pro-inflammatory cytokine IL-6. We recently showed that mouse embryonic fibroblasts (MEFs) derived from STAT3C k/in mice, which express physiological levels of the constitutively active mutant STAT3C, display features of transformed cells such as increased proliferation, resistance to apoptosis and senescence, and aerobic glycolysis. Here, we show that pre-existing constitutively active STAT3 is sufficient to prime primary MEFs for malignant transformation upon spontaneous immortalization. Transformation is strictly STAT3-dependent and correlates with high resistance to apoptosis and enhanced expression of anti-apoptotic/pro-survival genes. Additionally, hypoxia inducible factor (HIF)-1α level is elevated by twofold and contributes to STAT3 oncogenic activity by supporting high rates of aerobic glycolysis. Thus, constitutively active STAT3, an accepted essential factor for tumor growth/progression, can also act as a first hit in multistep carcinogenesis; this ability to predispose cells to malignant transformation may be particularly relevant in the pro-oncogenic niche represented by chronically inflamed tissues.",
keywords = "3T3 MEFs, aerobic glycolysis, apoptosis, HIF-1α, STAT3, tumorigenesis",
author = "M. Demaria and S. Misale and C. Giorgi and V. Miano and A. Camporeale and J. Campisi and P. Pinton and V. Poli",
year = "2012",
month = "8",
doi = "10.1038/cdd.2012.20",
language = "English",
volume = "19",
pages = "1390--1397",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - STAT3 can serve as a hit in the process of malignant transformation of primary cells

AU - Demaria, M.

AU - Misale, S.

AU - Giorgi, C.

AU - Miano, V.

AU - Camporeale, A.

AU - Campisi, J.

AU - Pinton, P.

AU - Poli, V.

PY - 2012/8

Y1 - 2012/8

N2 - The transcription factor signal transducer and activator of transcription 3 (STAT3) acts downstream of many pro-oncogenic signals, including cytokines, growth factors and oncogenes, and is accordingly constitutively active in a wide variety of tumors that often become addicted to it. Moreover, STAT3 is a key player in mediating inflammation-driven tumorigenesis, where its aberrant continuous activation is typically triggered by local or systemic production of the pro-inflammatory cytokine IL-6. We recently showed that mouse embryonic fibroblasts (MEFs) derived from STAT3C k/in mice, which express physiological levels of the constitutively active mutant STAT3C, display features of transformed cells such as increased proliferation, resistance to apoptosis and senescence, and aerobic glycolysis. Here, we show that pre-existing constitutively active STAT3 is sufficient to prime primary MEFs for malignant transformation upon spontaneous immortalization. Transformation is strictly STAT3-dependent and correlates with high resistance to apoptosis and enhanced expression of anti-apoptotic/pro-survival genes. Additionally, hypoxia inducible factor (HIF)-1α level is elevated by twofold and contributes to STAT3 oncogenic activity by supporting high rates of aerobic glycolysis. Thus, constitutively active STAT3, an accepted essential factor for tumor growth/progression, can also act as a first hit in multistep carcinogenesis; this ability to predispose cells to malignant transformation may be particularly relevant in the pro-oncogenic niche represented by chronically inflamed tissues.

AB - The transcription factor signal transducer and activator of transcription 3 (STAT3) acts downstream of many pro-oncogenic signals, including cytokines, growth factors and oncogenes, and is accordingly constitutively active in a wide variety of tumors that often become addicted to it. Moreover, STAT3 is a key player in mediating inflammation-driven tumorigenesis, where its aberrant continuous activation is typically triggered by local or systemic production of the pro-inflammatory cytokine IL-6. We recently showed that mouse embryonic fibroblasts (MEFs) derived from STAT3C k/in mice, which express physiological levels of the constitutively active mutant STAT3C, display features of transformed cells such as increased proliferation, resistance to apoptosis and senescence, and aerobic glycolysis. Here, we show that pre-existing constitutively active STAT3 is sufficient to prime primary MEFs for malignant transformation upon spontaneous immortalization. Transformation is strictly STAT3-dependent and correlates with high resistance to apoptosis and enhanced expression of anti-apoptotic/pro-survival genes. Additionally, hypoxia inducible factor (HIF)-1α level is elevated by twofold and contributes to STAT3 oncogenic activity by supporting high rates of aerobic glycolysis. Thus, constitutively active STAT3, an accepted essential factor for tumor growth/progression, can also act as a first hit in multistep carcinogenesis; this ability to predispose cells to malignant transformation may be particularly relevant in the pro-oncogenic niche represented by chronically inflamed tissues.

KW - 3T3 MEFs

KW - aerobic glycolysis

KW - apoptosis

KW - HIF-1α

KW - STAT3

KW - tumorigenesis

UR - http://www.scopus.com/inward/record.url?scp=84863723266&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863723266&partnerID=8YFLogxK

U2 - 10.1038/cdd.2012.20

DO - 10.1038/cdd.2012.20

M3 - Article

VL - 19

SP - 1390

EP - 1397

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

IS - 8

ER -