Pancreatic cancer is characterized by extremely poor prognosis because of early recurrence and
metastasis, and increasing evidence supports the critical role of microRNA in cancer progression. Here we
identified that microRNA-34b functioned as a tumor-suppressing microRNA by targeting oncogenic Smad3 in
pancreatic cancer. As a hypovascular tumor with a potential endoplasmic reticulum stress microenvironment,
miR-34b was silenced after ER stress inducer thapsigargin (Tg) treatment and negatively regulated by ER
stress chaperone glucose regulated protein 78 (GRP78) in pancreatic cancer cells. In human specimens, we
found that miR-34b was down-regulated in pancreatic cancer tissues and low level of miR-34b expression was
positively correlated with tumor-node-metastasis (TNM) stage, lymph-node metastasis and overall survival.
Functional assays showed that over-expression of miR-34b inhibited pancreatic cancer progression in vitro and
in vivo. In addition, Smad3 was demonstrated as a direct target of miR-34b and negatively regulated by miR-
34b at mRNA and protein levels. Luciferase assays confirmed that miR-34b could directly bind to the
3’untranslated region of Smad3. An inverse correlation between miR-34b and Smad3 was observed in 64
pancreatic cancer tissues. Our findings indicate that miR-34b acts as a tumor metastasis suppressor through
negatively modulating Smad3, which may provide a potential therapeutic strategy for pancreatic cancer.
Keywords: EMT, endoplasmic reticulum stress, microRNA-34b, pancreatic cancer, Smad3, tumor suppressor
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