Seminars & Speakers

Stat3 is a potential therapeutic target for cancer stem cells & tumor microenvironment
Speaker Sang-Kyu Ye
Affiliation Seoul National University College of Medicine
Date November 16, 2017
Time 4:00 pm - 5:30 pm
Venue Room N104, Bldg 110
Sponsor UNIST-Life Sciences
Host Chan Young Park
Contact cypark@unist.ac.kr
Phone 2539
Signal transducer and activator of transcription 3 (STAT3), which is a member of the Janus kinase (JAK)-STAT signaling pathway, mediates cytokine signaling and regulates the transcription of various genes. Our previous study has clearly shown that STAT3 modulates hypoxia inducible factor 1α (HIF-1α) protein stability and enhances HIF-1-mediated expression of VEGF in hypoxic solid tumors.
We also developed a tamoxifen-resistant MCF-7 (TRM-7) cell line to elucidate the molecular mechanisms and factors associated with acquisition of such resistance. We showed that phosphorylation of STAT3 at tyrosine 705 (Y705) and RANTES expression are increased in response to tamoxifen in human breast cancer cells. On the basis of these results, we hypothesize that upregulated STAT3 phosphorylation and RANTES may be correlated with the development of drug resistance. Here, we showed that STAT3 and RANTES contribute to the maintenance of drug resistance. STAT3 phosphorylation is constitutively retained via a RANTES autocrine loop, which in turn upregulates anti-apoptotic signals in TRM-7 cells. STAT3-RANTES autocrine signaling affected expression of anti-apoptotic BCL-2 family genes and prevented TRM-7 cells from undergoing programmed cell death by inhibiting PARP and caspase-9 cleavage. Subsequently, blockade of STAT3 and RANTES in TRM-7 cells resulted in reduction of anti-apoptotic signals, which was rescued by exogenous RANTES treatment; drug resistance was also restored. Taken together, our results suggested that STAT3-RANTES autocrine signaling is essential for maintenance of drug resistance and inhibition of programmed cell death. These mechanisms of STAT3-RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors.
Recently, we demonstrate that CD133, as cancer stem cell marker, up-regulation requires STAT3 phosphorylation, showing that CD133 expression is directly regulated by STAT3 upon IL-6 and IL-23 stimulations in HCC cells. Moreover, our findings demonstrate that STAT3 activation in ECs promotes tumor metastasis through the induction of cell adhesion molecules, demonstrating a role for ECs in response to tumor cells during tumor metastasis. Consequently, our research will ultimately lead to the development of better molecular markers for cancer stem cells and tumor microenvironment in solid tumors.
 
​