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 1a (HIF-1a)-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-1a/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-1a and IL-6. Finally, in a xenograft model, overexpressing miR-338-5p in CRC cells and HIF-1a inhibitor PX-478 were able to enhance the sensitivity of CRC to oxaliplatin (OXA) via suppressing the HIF-1a/miR-338-5p/IL-6 feedback loop in vivo. Taken together, our results uncovered an HIF-1a/ miR-338-5p/IL-6 feedback circuit that is critical in hypoxiamediated drug resistance in CRC; targeting each member of this feedback loop could potentially reverse hypoxia-induced drug resistance in CRC.

The schematic of metamaterials applied in wireless power transfer.

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The flexible metacomposites with tunable negative permittivity have great potential in wearable cloaks, stretchable sensors, and thin-film capacitors, etc. In this paper, the flexible graphene/polydimethyl­siloxane (GR/PDMS) metacomposites with tunable negative permittivity were prepared by an in situ polymerization method. The ac conductivity behavior, dielectric property, and impedance performance of the resulting composites with different graphene mass ratios (0–4 wt %) were studied. With the increase of graphene, the conductive mechanism of the resulting composites changed from hopping conduction to electron conduction, along with the change of microstructure. When graphene content in the composites came up to 3 wt %, the negative permittivity conforming to Drude model was observed. Further investigation revealed that there is a corresponding relationship between the permittivity and the reactance. It is demonstrated that the inductive character is responsible for the negative permittivity, while the capacitive character results in the positive permittivity.

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