Exosomal Linc00969 induces trastuzumab resistance in breast cancer by increasing HER-2 protein expression and mRNA stability by binding to HUR.

BACKGROUND: Breast cancer (BC) is the most common malignant disease in female patients worldwide. In HER-2+ BC patients, trastuzumab therapy is associated with a better prognosis. However, many HER-2+ BC patients experience recurrence or metastasis because of trastuzumab resistance. The mechanisms underlying trastuzumab resistance remain unclear. Recently, substantial evidence has suggested that exosomes are associated with drug resistance, and lncRNAs have attracted increasing attention due to their potential role in the regulation of trastuzumab resistance. METHODS: We collected the exosomes from the plasma of BC patients with and without trastuzumab resistance, sequenced the whole transcriptomes, identified differentially expressed lncRNAs, and identified lncRNA Linc00969, which was overexpressed in trastuzumab-resistant patients. Then, we established trastuzumab-resistant BC cell lines and explored the role of exosomal Linc00969 in trastuzumab resistance in vitro and in vivo by silencing or overexpressing Linc00969 and performing a series of functional analyses. Furthermore, to explore the mechanism by which exosomal Linc00969 contributes to trastuzumab resistance, we measured changes in HER-2, HUR and autophagy-related protein expression levels after regulating Linc00969 expression. In addition, we investigated the interaction between Linc00969 and HUR via pull-down and RIP assays and the effect of HUR on HER-2 expression and trastuzumab resistance after blocking HUR. RESULTS: We first found that exosomal lncRNA Linc00969 was overexpressed in trastuzumab-resistant BC patients and that exosome-mediated Linc00969 transfer could disseminate trastuzumab resistance in BC. Then, we found that silencing Linc00969 could reduce trastuzumab resistance and that overexpressing Linc00969 could enhance trastuzumab resistance. Furthermore, our results showed that Linc00969 could upregulate HER-2 expression at the protein level and maintain the stability of HER-2 mRNA by binding to HUR. Additionally, we found that exosomal Linc00969 could regulate trastuzumab resistance by inducing autophagy. CONCLUSIONS: In this study, we first identified that exosomal lncRNA Linc00969 could induce trastuzumab resistance by increasing HER-2 protein expression and mRNA stability by binding to HUR, and Linc00969 might also be involved in trastuzumab resistance by inducing autophagy. Our results elucidate a novel mechanism underlying trastuzumab resistance, and Linc00969 might be a new target for improving the treatment of HER-2+ BC patients.

Chlorination of microcystin-LR in natural water: Kinetics, transformation products, and genotoxicity.

Microcystin-LR (MC-LR), a type of cyanotoxin commonly found in natural water bodies (sources of drinking water), poses a threat to human health due to its high toxicity. It is essential to successfully remove this cyanotoxin from drinking water sources. In this study, chlorine was used to oxidize MC-LR in Milli-Q water (MQ) (control test) and natural water collected from Lake Longhu (LLW) as a drinking water source. The removal efficiency, proposed transformation pathways, and genotoxicity were investigated. In the chlorine dose range investigated (4.0 mg L-1 - 8.0 mg L-1), the apparent second-order rate constants for MC-LR chlorination varied from 21.3 M-1s-1 to 31.9 M-1s-1 in MQ, higher than that in LLW (9.06 M-1s-1 to 17.7 M-1s-1) due to a faster chlorine decay attributed to the water matrix (e.g., natural organic matter) of LLW. Eleven transformation products (TPs) of MC-LR were identified in the two waters. The conjugated diene moieties and benzene ring of Adda moiety (3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid), and the double bond of Mdha moiety (N-methyldehydroalanine) were the major susceptible reaction sites. Attacking unsaturated bonds by hydroxyl and chlorine radicals to generate monochloro-hydroxy-MC-LR was the primary initial transformation pathway, followed by nucleophilic substitution, dehydration, and cleavage in MC-LR. Chlorine substitution on the benzene ring was also observed. Based on the bacterial reverse-mutation assay (Ames assay), TPs in treated natural water did not induce genotoxicity/mutagenicity. These findings shed light on the role of chlorination in controlling the risk of cyanotoxins in drinking water treatment plants.

Design and synthesis of broadband absorption covalent organic framework for efficient artificial photocatalytic amine coupling.

Developing highly active materials that efficiently utilize solar spectra is crucial for photocatalysis, but still remains a challenge. Here, we report a new donor-acceptor (D-A) covalent organic framework (COF) with a wide absorption range from 200 nm to 900 nm (ultraviolet-visible-near infrared light). We find that the thiophene functional group is accurately introduced into the electron acceptor units of TpDPP-Py (TpDPP: 5,5'-(2,5-bis(2-ethylhexyl)-3,6-dioxo-2,3,5,6-tetrahydropyrrolo [3,4-c]pyrrole-1,4-diyl)bis(thiophene-2-carbaldehyde), Py: 1,3,6,8-tetrakis(4-aminophenyl)pyrene) COFs not only significantly extends its spectral absorption capacity but also endows them with two-photon and three-photon absorption effects, greatly enhancing the utilization rate of sunlight. The selective coupling of benzylamine as the target reactant is used to assess the photocatalytic activity of TpDPP-Py COFs, showing high photocatalytic conversion of 99% and selectivity of 98% in 20 min. Additionally, the TpDPP-Py COFs also exhibit the universality of photocatalytic selective coupling of other imine derivatives with ~100% conversion efficiency. Overall, this work brings a significant strategy for developing COFs with a wide absorption range to enhance photocatalytic activity.