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On-target PIM-1 And STAT3 Inhibition Thwarts Disease Progression In Xenografts Of Gastric Cancer Stem-like Cells | 29468
ISSN: 2161-069X
Journal of Gastrointestinal & Digestive System
Open Access
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Background: Peritoneal dissemination is characterized by an aggressive clinical course, therapeutic resistance and striking
molecular heterogeneity. Cancer stem-like cells (CSCs) closely model this molecular heterogeneity and likely have a key role in
tumor recurrence and therapeutic resistance. Emerging evidence indicates that signal transducer and activator of transcription
3 (STAT3) is an important mediator of tumor cell survival, growth and invasion in peritoneal dissemination that correlated with
PIM-1 expression. Herein, we generated characterized 12 clones cells populations in gastric tumors with distinct properties that
have stem cell-like characteristics to evaluate the translational potential therapeutics by PIM-1 inhibitors.
Methods: CSCs were cultured in Doxorubicin resistant condition; condense sphericity and highly expression of stem cells
marker (CD133, CD44, DLL4 and LGR5) were determined by soft agar, real-time PCR. Endogenous PIM-1 and STAT3 activity
was assessed in human gastric tissue, CSCs and animal xenografts by immunohistochemistry, PET/CT and Western blotting.
PIM-1 inhibitors were used to inhibit PIM-1 and STAT3 activity in vitro and in vivo.
Results: Both PIM-1 and STAT3 activity was demonstrated to be highly activated in human gastric tissue, molecularly
heterogeneous CSCs tumors and CSCs xenografts. PIM-1 inhibitors or PIM-1 siRNA knockdown administration resulted in ontarget
STAT3 inhibition and dramatically reduced CSCs survival, soft agar assay and stem cells markers. CSCs animal xenografts
maintained high levels of activated PIM-1 and STAT3 activity seen in their parent tumors. Intra-peritoneal PIM-1 inhibitors
reduced intra-tumoral PIM-1 and STAT3 activity, stem cells marker and prolonged animal survival.
Conclusion: Our study demonstrates the in vitro and in vivo efficacy of on-target PIM-1 and STAT3 inhibition in heterogeneous
CSCs that closely emulate the genomic and tumorigenic characteristics of molecular heterogeneity in cancer stem-like cells.
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