Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth.
Colorectal carcinoma (CRC) is a major cause of morbidity and mortality in Western countries. It has so far been molecularly defined mainly by alterations of the Wnt pathway. We show here for the first time that aberrant activities of the signal transducer and activator of transcription STAT3 actively contribute to this malignancy and, thus, are a potential therapeutic target for CRC. Constitutive STAT3 activity was found to be abundant in dedifferentiated cancer cells and infiltrating lymphocytes of CRC samples, but not in non-neoplastic colon epithelium. Cell lines derived from malignant colorectal tumors lost persistent STAT3 activity in culture. However, implantation of colon carcinoma cells into nude mice resulted in restoration of STAT3 activity, suggesting a role of an extracellular stimulus within the tumor microenvironment as a trigger for STAT activation. STAT3 activity in CRC cells triggered through interleukin-6 or through a constitutively active STAT3 mutant promoted cancer cell multiplication, whereas STAT3 inhibition through a dominant-negative variant impaired IL-6-driven proliferation. Blockade of STAT3 activation in CRC-derived xenograft tumors slowed down their development, arguing for a contribution of STAT3 to colorectal tumor growth.
Corvinus
Florian M
FM
Institute of Biochemistry I, Friedrich-Schiller University Jena Medical School, Jena, Germany.
Orth
Carina
C
Moriggl
Richard
R
Tsareva
Svetlana A
SA
Wagner
Stefan
S
Pfitzner
Edith B
EB
Baus
Daniela
D
Kaufmann
Roland
R
Huber
Lukas A
LA
Zatloukal
Kurt
K
Beug
Hartmut
H
Ohlschläger
Peter
P
Schütz
Alexander
A
Halbhuber
Karl-Jürgen
KJ
Friedrich
Karlheinz
K
D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000473:pathology; D004247:DNA / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012190:Retroviridae / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D013997:Time Factors
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004247:DNA