Guangtao Luo

Abstract Exosomes are emerging as important mediators of the cross-talk between tumor cells and the microenvironment. However, the mechanisms by which exosomes modulate tumor development under hypoxia in pancreatic cancer remain largely unknown. Here, we found that hypoxic exosomes derived from pancreatic cancer cells activate macrophages to the M2 phenotype in a HIF1a or HIF2a–dependent manner, which then facilitates the migration, invasion, and epithelial–mesenchymal transition of pancreatic cancer cells. Given that exosomes have been shown to transport miRNAs to alter cellular functions, we discovered that miR-301a-3p was highly expressed in hypoxic pancreatic cancer cells and enriched in hypoxic pancreatic cancer cell–derived exosomes. Circulating exosomal miR-301a-3p levels positively associated with depth of invasion, lymph node metastasis, late TNM stage, and poor prognosis of pancreatic cancer. Hypoxic exosomal miR-301a-3p induced the M2 polarization of macrophages via activation of the PTEN/PI3Kγ signaling pathway. Coculturing of pancreatic cancer cells with macrophages in which miR-301a-3p was upregulated or treated with hypoxic exosomes enhanced their metastatic capacity. Collectively, these data indicate that pancreatic cancer cells generate miR-301a-3p–rich exosomes in a hypoxic microenvironment, which then polarize macrophages to promote malignant behaviors of pancreatic cancer cells. Targeting exosomal miR-301a-3p may provide a potential diagnosis and treatment strategy for pancreatic cancer. Significance: These findings identify an exosomal miRNA critical for microenvironmental cross-talk that may prove to be a potential target for diagnosis and treatment of pancreatic cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4586/F1.large.jpg. Cancer Res; 78(16); 4586–98. ©2018 AACR.

BACKGROUND: We previously showed that miR-301a-3p affects the invasion and migration abilities of pancreatic cancer cells. Here, we explore the role of miR-301a-3p in chemoresistance, which represents a major obstacle in cancer treatment. METHODS: . We used quantitative real-time PCR (qRT-PCR) to measure miR-301a-3p expression in wild-type and gemcitabine-resistant pancreatic cancer cells. We performed Western blot, qRT-PCR, and luciferase and rescue assays to confirm the direct target of miR-301a-3p. RESULTS: . The role of miR-301-3p in chemoresistance was dependent on PTEN. The suppression of miR-301-3p expression sensitized pancreatic cancer cells to gemcitabine chemotherapy in a xenograft mouse model. CONCLUSION: MiR-301a-3p confers resistance to gemcitabine by regulating the expression of PTEN. The co-delivery of miR-301a-3p and gemcitabine might be an effective therapeutic regimen for patients with pancreatic cancer.

In the original version of [this article][1] ([1][2]), the image depicting the effect of macrophages treated with PANC-1-H-exo and transfected with PI3Kγ siRNA on pancreatic cancer cells invasion in the bottom left panel of Fig. 5L is incorrect. The error has been corrected in the latest online

The PI3K/Akt pathway is an attractive therapeutic target in the treatment of pancreatic cancer, as it was demonstrated to be aberrantly regulated in pancreatic cancer cells. The present study aimed to investigate the therapeutic potential of the novel Akt inhibitor MK-2206 in human pancreatic cancer cell lines. Pancreatic cancer cell survival following MK-2206 treatment was assessed using the Cell Counting Kit-8 (CCK-8) assay, colony formation and determination of the apoptotic rate by flow cytometry following annexin-V-fluorescein isothiocyanate/propidium iodide staining. The effects of MK-2206 alone or in combination with gemcitabine on pancreatic cell proliferation were assessed using the CCK-8 assay. Western blotting was used to examine the effects of the two drugs on Akt protein expression. The results demonstrated that MK-2206 inhibited the proliferation and induced apoptosis of the Mia PaCa-2 and Panc-1 pancreatic cancer cell lines. In addition, CCK-8 cytotoxicity test showed that combined administration of MK-2206 with gemcitabine enhanced the cytotoxic efficacy of gemcitabine. Furthermore, a low dose of MK-2206 (1 µM) combined with gemcitabine was enough to inhibit Akt phosphorylation. Taken together, these results provided some insight into the underlying mechanism of the anticancer effects of MK-2206 on pancreatic cancer cells.