Stat3 and tumor cell proliferation

Schick, Nicole. Stat3 and tumor cell proliferation. 2004, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_6697

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In the more prosperous countries of the world cancer is the cause of death of roughly
one person in five; the five most common cancers are those of the prostate, breast,
lung, colon/rectum and the uterine cervix. Cancer is caused by the stepwise
acquisition of mutations that allow: limitless replicative potential, insensitivity to
anti-growth signals, evasion of apoptosis, self-sufficiency in growth signals, tissue
sustained angiogenesis and invasion and metastasis. Two obvious targets for cancer
drug development are the two cooperating conditions that permit cell expansion;
deregulated cell proliferation and inhibition of apoptosis.Stat3, a member of the Signal transducers and activators of transcription (STAT)
protein family of transcription factors, seems to play a role in cancer progression
since it is constitutively activated in a wide variety of human malignancies. In
addition, constitutively active Stat3 is involved in growth promoting and apoptosis
inhibiting functions in tumor cells. On the other hand cytokine induced activation of
Stat3 can lead to growth inhibition and apoptosis in some normal and cancerous cells.
The precise contribution of Stat3 to these different scenarios in cancer cells could not
be elucidated so far, which makes it difficult to target Stat3 in cancer therapy. The
aim of this thesis was to investigate the mechanism by which Stat3 controls
proliferation of tumor cells that are proliferatively inhibited by IL-6 type cytokine
treatment. Dimerization of IL-6 type cytokine receptors, upon ligand binding, leads
not only to activation of the JAK-STAT pathway, but also to activation of the
mitogen activated protein kinase (MAPK) pathway and the phosphatidylinositol
dependant kinase (PI3K) signaling cascade. To investigate the participation of Stat3
in IL-6 induced anti-proliferative effects without the influence of the other pathways,
we have designed an inducible Stat3 construct, in which the entire Stat3 coding
sequence was fused to the estrogen receptor ligand-binding domain (ER-LBD) that
can be dimerized by addition of 4-hydroxytamoxifen (4HT). Stable expression of this construct in A375 melanoma cells and stimulation with 4HT
showed that Stat3 activation alone is sufficient for the anti-proliferative effects
induced by IL-6 type cytokine stimulation. Surprisingly, treatment of cells with a combination of OSM and 4HT, led to strong and prolonged Stat3 activity, and
induced cell cycle arrest and apoptosis. These results suggest that Stat3 activation in
cancer cells, in which IL-6 has anti-proliferative effects, leads to inhibition in tumor
cell proliferation, whereas strong and prolonged activation of Stat3 induces apoptosis.
Therefore, for cancer therapy it might be desirable to induce Stat3 activation in these
specific cases. Additionally, we identified the Stat3 target genes that play a role in the observed
biological effects. Using oligonucleotide microarray analysis and small interfering
(si) RNA targeting, we showed that the transcription factor C/EBPδ, a Stat3 target, is
a mediator of Stat3 anti-proliferative effects. Furthermore, using the same techniques,
we found a novel Stat3 target, the transcription factor TEL (ETV6), which we
identified as a negative regulator of Stat3 activity and Stat3 induced biological
functions. The mechanism whereby TEL inhibits Stat3 activity was further
investigated. Stat3 inhibition by TEL requires histone deacetylase (HDAC) activity
since addition of Trichostatin A (TSA), a general HDAC inhibitor, blocked TEL
mediated repression. The pointed domain of TEL was identified as being essential for
Stat3 inhibition. Interestingly, the DNA binding domain mutant of TEL was still able
to repress Stat3 activity. Moreover, TEL and Stat3 interact since TEL was detected in
immunoprecipitates of Stat3. Taken together our data show that TEL is a newly identified Stat3 target that
represses Stat3 transcriptional activity by interacting with Stat3 and recruiting
HDACs to the transcriptional complex. Therefore, we suggest that TEL might be part
of a novel negative feedback loop in the Stat3 signaling cascade.
Advisors:Hynes, Nancy
Committee Members:Matthias, Patrick D. and Badache, Ali
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:6697
Thesis status:Complete
Number of Pages:157
Identification Number:
edoc DOI:
Last Modified:23 Feb 2018 11:40
Deposited On:13 Feb 2009 14:44

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