Ke Xu

// Limin Wang 1, * , Limin Cao 1, * , Huimin Wang 1, * , Boning Liu 1 , Qicheng Zhang 1 , Zhaowei Meng 2 , Xiang Wu 3 , Qinghua Zhou 1 and Ke Xu 1 1 Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenviroment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China 2 Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China 3 Core Facility Center, Tianjin Medical University General Hospital, Tianjin 300052, China * These authors have contributed equally to this work Correspondence to: Ke Xu, email: ke_xu@hotmail.com Keywords: lung cancer, cancer-associated fibroblasts, metastasis, EMT, IL-6 Received: December 08, 2016      Accepted: June 02, 2017      Published: June 28, 2017 ABSTRACT Recent studies indicate that cancer-associated fibroblasts (CAFs) are involved in tumor growth, invasion and metastasis, however, the underling mechanisms remain unclear. In the present study, we investigated the role of CAFs on the metastatic potential of lung cancer cells. The stromal fibroblasts we isolated from lung cancer tissues presented CAFs characteristics with high levels of α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP). Our data showed that the conditioned medium from cultured CAFs (CAF-CM) dramatically enhanced migration and invasion of lung cancer cells. CAF-CM induced epithelial-mesenchymal transition (EMT) by regulating the expression of EMT-associated markers E-cadherin and vimentin, and also modulated metastasis-related genes MMP-2 and VEGF both in vitro and in vivo . Further mechanistic studies demonstrated that CAFs enhanced the metastatic potential of lung cancer cells by secreting IL-6, subsequently activating of JAK2/STAT3 signaling pathway. Additionally, the inhibition of IL-6/STAT3 signaling pathway by IL-6 neutralizing antibody or specific inhibitors of JAK2/STAT3 reversed CAF-CM induced EMT and migration of lung cancer cells. Taken together, these findings revealed a novel mechanism that CAFs induced EMT and promoted metastasis of lung cancer cells through the IL-6/STAT3 signaling pathway.

Systematic bone loss is commonly complicated with inflammatory bowel diseases (IBDs) with unclear pathogenesis and uncertain treatment. In experimental colitis mouse models established by dextran sulfate sodium and IL-10 knockout induced with piroxicam, bone mass and quality are significantly decreased. Colitis mice demonstrate a lower bone formation rate and fewer osteoblasts in femur. Bone marrow mesenchymal stem/stromal cells (BMSCs) from colitis mice tend to differentiate into adipocytes rather than osteoblasts. Serum from patients with IBD promotes adipogenesis of human BMSCs. RNA sequencing reveals that colitis downregulates Wnt signaling in BMSCs. For treatment, exosomes with Golgi glycoprotein 1 inserted could carry Wnt agonist 1 and accumulate in bone via intravenous administration. They could alleviate bone loss, promote bone formation, and accelerate fracture healing in colitis mice. Collectively, BMSC commitment in inflammatory microenvironment contributes to lower bone quantity and quality and could be rescued by redirecting differentiation toward osteoblasts through bone-targeted drug delivery.

Hypoxia is associated with poor prognosis and therapeutic resistance in cancer patients. Accumulating evidence has shown that microRNA (miRNA) plays an important role in the acquired drug resistance in colorectal carcinoma (CRC). However, the role of miRNA in hypoxia-induced CRC drug resistance remains to be elucidated. Here, we identified a hypoxia-triggered feedback loop that involves hypoxia-inducible transcription factor 1α (HIF-1α)-mediated repression of miR-338-5p and confers drug resistance in CRC. In this study, the unbiased miRNA array screening revealed that miR-338-5p is downregulated in both hypoxic CRC cell lines tested. Repression of miR-338-5p was required for hypoxia-induced CRC drug resistance. Furthermore, we identified interleukin-6 (IL-6), which mediates STAT3/Bcl2 activation under hypoxic conditions, as a direct miR-338-5p target. The resulting HIF-1α/miR-338-5p/IL-6 feedback loop was necessary for drug resistance in colon cancer cell lines. Using CRC patient samples, we found miR-338-5p has a negative correlation with HIF-1α and IL-6. Finally, in a xenograft model, overexpressing miR-338-5p in CRC cells and HIF-1α inhibitor PX-478 were able to enhance the sensitivity of CRC to oxaliplatin (OXA) via suppressing the HIF-1α/miR-338-5p/IL-6 feedback loop in vivo. Taken together, our results uncovered an HIF-1α/miR-338-5p/IL-6 feedback circuit that is critical in hypoxia-mediated drug resistance in CRC; targeting each member of this feedback loop could potentially reverse hypoxia-induced drug resistance in CRC. Hypoxia is associated with poor prognosis and therapeutic resistance in cancer patients. Accumulating evidence has shown that microRNA (miRNA) plays an important role in the acquired drug resistance in colorectal carcinoma (CRC). However, the role of miRNA in hypoxia-induced CRC drug resistance remains to be elucidated. Here, we identified a hypoxia-triggered feedback loop that involves hypoxia-inducible transcription factor 1α (HIF-1α)-mediated repression of miR-338-5p and confers drug resistance in CRC. In this study, the unbiased miRNA array screening revealed that miR-338-5p is downregulated in both hypoxic CRC cell lines tested. Repression of miR-338-5p was required for hypoxia-induced CRC drug resistance. Furthermore, we identified interleukin-6 (IL-6), which mediates STAT3/Bcl2 activation under hypoxic conditions, as a direct miR-338-5p target. The resulting HIF-1α/miR-338-5p/IL-6 feedback loop was necessary for drug resistance in colon cancer cell lines. Using CRC patient samples, we found miR-338-5p has a negative correlation with HIF-1α and IL-6. Finally, in a xenograft model, overexpressing miR-338-5p in CRC cells and HIF-1α inhibitor PX-478 were able to enhance the sensitivity of CRC to oxaliplatin (OXA) via suppressing the HIF-1α/miR-338-5p/IL-6 feedback loop in vivo. Taken together, our results uncovered an HIF-1α/miR-338-5p/IL-6 feedback circuit that is critical in hypoxia-mediated drug resistance in CRC; targeting each member of this feedback loop could potentially reverse hypoxia-induced drug resistance in CRC.