Multiple-matrix metabolomics analysis for the distinct detection of colorectal cancer and adenoma.

OBJECTIVES: Although colorectal cancer (CRC) is the leading cause of cancer-related morbidity and mortality, current diagnostic tests for early-stage CRC and colorectal adenoma (CRA) are suboptimal. Therefore, there is an urgent need to explore less invasive screening procedures for CRC and CRA diagnosis. METHODS: Untargeted gas chromatography-mass spectrometry (GC-MS) metabolic profiling approach was applied to identify candidate metabolites. We performed metabolomics profiling on plasma samples from 412 subjects including 200 CRC patients, 160 CRA patients and 52 normal controls (NC). Among these patients, 45 CRC patients, 152 CRA patients and 50 normal controls had their fecal samples tested simultaneously. RESULTS: Differential metabolites were screened in the adenoma-carcinoma sequence. Three diagnostic models were further developed to identify cancer group, cancer stage, and cancer microsatellite status using those significant metabolites. The three-metabolite-only classifiers used to distinguish the cancer group always keeps the area under the receiver operating characteristic curve (AUC) greater than 0.7. The AUC performance of the classifiers applied to discriminate CRC stage is generally greater than 0.8, and the classifiers used to distinguish microsatellite status of CRC is greater than 0.9. CONCLUSION: This finding highlights potential early-driver metabolites in CRA and early-stage CRC. We also find potential metabolic markers for discriminating the microsatellite state of CRC. Our study and diagnostic model have potential applications for non-invasive CRC and CRA detection.

Arenobufagin enhances T-cell anti-tumor immunity in colorectal cancer by modulating HSP90ß accessibility.

BACKGROUND: Colorectal cancer (CRC) is a significant public health issue, ranking as one of the predominant cancer types globally in terms of incidence. Intriguingly, Arenobufagin (Are), a compound extracted from toad venom, has demonstrated the potential to inhibit tumor growth effectively. PURPOSE: This study aimed to explore Are's molecular targets and unravel its antitumor mechanism in CRC. Specifically, we were interested in its impact on immune checkpoint modulation and correlations with HSP90ß-STAT3-PD-L1 axis activity. METHODS: We investigated the in vivo antitumor effects of Are by constructing a colorectalcancer subcutaneous xenograft mouse model. Subsequently, we employed single-cell multi-omics technology to study the potential mechanism by which Are inhibits CRC. Utilizing target-responsive accessibility profiling (TRAP) technology, we identified heatshock protein 90ß (HSP90ß) as the direct target of Are, and confirmed this through a microscale thermophoresis experiment (MST). Further downstream mechanisms were explored through techniques such as co-immunoprecipitation, Western blotting, qPCR, and immunofluorescence. Concurrently, we arrived at the same research conclusion at the organoid level by co-cultivating with immune cells. RESULTS: We observed that Are inhibits PD-Ll expression in CRC tumor xenografts at low concentrations. Moreover, TRAP revealed that HSP90ß's accessibility significantly decreased upon Are binding. We demonstrated a decrease in the activity of the HSP90ß-STAT3-PD-Ll axis following low-concentration Are treatment in vivo. The PDO analysis showed improved enrichment of lymphocytes, particularly T cells, on the PDOs following Are treatment. CONCLUSION: Contrary to previous research focusing on the direct cytotoxicity of Are towards tumor cells, our findings indicate that it can also inhibit tumor growth at lower concentrations through the modulation of immune checkpoints. This study unveils a novel anti-tumor mechanism of Are and stimulates contemplation on the dose-response relationship of natural products, which is beneficial for the clinical translational application of Are.

Sophocarpine alleviates intestinal fibrosis via inhibition of inflammation and fibroblast into myofibroblast transition by targeting the Sirt1/p65 signaling axis.

In this study, we used alkaloids from Sophora flavescens to inhibit the SASP, leading to fibroblast-into-myofibroblast transition (FMT) to maintain intestinal mucosal homeostasis in vitro and in vivo. We used western blotting (WB) and immunofluorescence staining (IF) to assess whether five kinds of alkaloids inhibit the major inflammatory pathways and chose the most effective compound (sophocarpine; SPC) to ameliorate colorectal inflammation in a dextran sulfate sodium (DSS)-induced UC mouse model. IF, Immunohistochemistry staining (IHC), WB, disease activity index (DAI), and enzyme-linked immunosorbent assay (ELISA) were conducted to investigate the mechanism of action of this compound. Next, we detected the pharmacological activity of SPC on the senescence-associated secretory phenotypes (SASP) and FMT in interleukin 6 (IL-6)-induced senescence-like fibroblasts and discussed the mucosal protection ability of SPC on a fibroblast-epithelium/organoid coculture system and organ-on-chip system. Taken together, our results provide evidence that SPC alleviates the inflammatory response, improves intestinal fibrosis and maintains intestinal mucosal homeostasis in vivo. Meanwhile, SPC was able to prevent IL-6-induced SASP and FMT in fibroblasts, maintain the expression of TJ proteins, and inhibit inflammation and genomic stability of colonic mucosal epithelial cells by activating SIRT1 in vitro. In conclusion, SPC treatment attenuates intestinal fibrosis by regulating SIRT1/NF-κB p65 signaling, and it might be a promising therapeutic agent for inflammatory bowel disease.

Multilayer Core-Sheath Wires with Radially Aligned N-Doped Carbon Nanohole Arrays for Boosting Energy Storage in Zinc-Ion Hybrid Supercapacitors.

Aqueous zinc-ion hybrid supercapacitors (ZHSCs) with the characteristics of low cost, long cycle stability, and good safety have been regarded as potential candidates for wearable energy storage applications. Herein, we reasonably designed a unique binder-free nitrogen-doped (N-doped) porous carbon@TiO2@Ti multilayer core-sheath wire (N-CTNT), which has vertical N-doped carbon nanoholes radially aligned on the wire surface. The unique structure and nitrogen dopants of N-CTNTs have facilitated zinc deposition on N-CTNT to form a hierarchical and robust zinc-carbon composite (Zn@N-CTNTs). A wire-shaped ZHSC was constructed with N-CTNTs and Zn@N-CTNTs as cathode and anode electrodes, respectively. The as-prepared ZHSC has an outstanding specific capacitance of 488 mF cm-2 at 1 mA cm-2. This hybrid supercapacitor also exhibits an excellent energy density of 211 µW h cm-2, good rate performance, and long cycle stability with a capacity retention rate of 90.4% after 16,000 cycles.

Overview of research progress and application of experimental models of colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy in terms of global tumor incidence, and the rates of morbidity and mortality due to CRC are rising. Experimental models of CRC play a vital role in CRC research. Clinical studies aimed at investigating the evolution and mechanism underlying the formation of CRC are based on cellular and animal models with broad applications. The present review classifies the different experimental models used in CRC research, and describes the characteristics and limitations of these models by comparing the research models with the clinical symptoms. The review also discusses the future prospects of developing new experimental models of CRC.

CCDC85C suppresses colorectal cancer cells proliferation and metastasis through activating GSK-3ß and promoting ß-catenin degradation.

Coiled-coil domain-containing 85C (CCDC85C) is a member of the DIPA family and contains a pair of conserved coiled-coil motifs, which was found to be related to a therapeutic target for colorectal cancer, however, its biological effects require further elucidation. This study aimed to determine the effect of CCDC85C on Colorectal Cancer (CRC) progression and to explore the related mechanism. pLV-PURO plasmid was used to construct CCDC85C-overexpressing cells while CRISPR-CasRx was used to construct CCDC85C knockdown cells. Effects of CCDC85C on cell proliferation, cycle and migration were examined using cell counting kit-8 assay, flow cytometry, wound healing assay and transwell assay. Immunofluorescence staining, immunoprecipitation, Western blot, co-immunoprecipitation and qPCR were performed to explore the mechanism. The overexpression of CCDC85C inhibited the proliferation and migration of HCT-116 and RKO cells in vitro and in vivo, but its knockdown promoted the proliferation of HCT-116 and RKO cells in vitro. Moreover, co-immunoprecipitation experiment confirmed that CCDC85C binding with GSK-3ß in RKO cells. Excess CCDC85C promoted phosphorylation and ubiquitination of ß-catenin. Our results suggested that CCDC85C binds to GSK-3ß to promote its activity and facilitates ubiquitination of ß-catenin. ß-catenin degradation is responsible for the inhibitory effect of CCDC85C on CRC cell proliferation and migration.

Interface Coordination Engineering of P-Fe3O4/Fe@C Derived from an Iron-Based Metal Organic Framework for pH-Universal Water Splitting.

Developing electrocatalysts with high energy conversion efficiency is urgently needed. In this work, P-Fe3O4/Fe@C electrodes with rich under-coordinated Fe atom interfaces are constructed for efficient pH-universal water splitting. The introduction of under-coordinated Fe atoms into the P-Fe3O4/Fe@C interface can increase the local charge density and polarize the 3d orbital lone electrons, which promotes water adsorption and activation to release more H*, thus elevating electrocatalytic activity. As a donor-like catalyst, P-Fe3O4/Fe@C displays excellent electrocatalytic performance with overpotentials of 160 mV and 214 mV in acidic and alkaline electrolytes at 10 mA cm-2, in addition to pH-universal long-term stability.

Liquid chromatography-tandem mass spectrometry analysis of a ratio-optimized drug pair of Sophora flavescens Aiton and Coptis chinensis Franch and study on the mechanism of anti-colorectal cancer effect of two alkaloids thereof.

The drug pair consisting of Sophora flavescens Aiton (Sophorae flavescentis radix, Kushen) and Coptis chinensis Franch. (Coptidis rhizoma, Huanglian), as described in Prescriptions for Universal Relief (Pujifang), is widely used to treat laxation. Matrine and berberine are the major active components of Kushen and Huanglian, respectively. These agents have shown remarkable anti-cancer and anti-inflammatory effects. A mouse model of colorectal cancer was used to determine the most effective combination of Kushen and Huanglian against anti-colorectal cancer. The results showed that the combination of Kushen and Huanglian at a 1:1 ratio exerted the best anti-colorectal cancer effect versus other ratios. Moreover, the anti-colorectal cancer effect and potential mechanism underlying the effects of matrine and berberine were evaluated by the analysis of combination treatment or monotherapy. In addition, the chemical constituents of Kushen and Huanglian were identified and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 67 chemical components were identified from the Kushen-Huanglian drug pair (water extraction), and the levels of matrine and berberine were 129 and 232 µg/g, respectively. Matrine and berberine reduced the growth of colorectal cancer and relieved the pathological conditions in mice. In addition, the combination of matrine and berberine displayed better anti-colorectal cancer efficacy than monotherapy. Moreover, matrine and berberine reduced the relative abundance of Bacteroidota and Campilobacterota at phylum level and that of Helicobacter, Lachnospiraceae_NK4A136_group, Candidatus_Arthromitus, norank_f_Lachnospiraceae, Rikenella, Odoribacter, Streptococcus, norank_f_Ruminococcaceae, and Anaerotruncus at the genus level. Western blotting results demonstrated that treatment with matrine and berberine decreased the protein expressions of c-MYC and RAS, whereas it increased that of sirtuin 3 (Sirt3). The findings indicated that the combination of matrine and berberine was more effective in inhibiting colorectal cancer than monotherapy. This beneficial effect might depend on the improvement of intestinal microbiota structure and regulation of the RAS/MEK/ERK-c-MYC-Sirt3 signaling axis.

α-hederin regulates glucose metabolism in intestinal epithelial cells by increasing SNX10 expression.

BACKGROUND: Sorting nexin 10 (SNX10) has recently been identified as a critical regulator of colorectal carcinogenesis, whose deletion promoted cell proliferation and survival in human CRC cells, and promoted colorectal tumor growth and upregulated amino-acid metabolism in mice. However, what happens when silencing SNX10 in normal human intestinal epithelial cells (IECs) remains unknown, and no drugs targeting SNX10 have been reported. Here, we first investigated the biological function and underlying mechanisms of SNX10 in normal human IECs, and found that α-hederin, a pentacyclic triterpenoid saponin, has a regulatory effect on SNX10 expression. PURPOSE: This study aimed to explore the function of SNX10 in IECs to provide a new target for the prevention and treatment of malignant transformation and the intervention mechanism of α-hederin for further development of potential novel agents targeting SNX10. METHODS: The transfection approach was used to construct SNX10 stable knockdown cells. Cell proliferation was detected by CCK8, clone formation, EdU, flow cytometry, and wound healing assays. Enzyme activity assays for glucose metabolism, qRT-PCR, western blotting, and immunofluorescence staining were performed to investigate the protein expression of signaling pathways. RESULTS: Silencing SNX10 promoted cell proliferation and cycle transition in IECs and increased the activity of key enzymes involved in glucose metabolism. Moreover, DEPDC5 expression was significantly decreased following SNX10 knockdown, followed by activation of the mTORC1 pathway. α-hederin reversed the accelerated cell proliferation, cycle progression, and glucose metabolic activity, as well as the activated mTORC1 pathway caused by SNX10 knockdown, by notably increasing SNX10 expression in a dose-dependent manner. CONCLUSION: We first reported that knockdown of SNX10 in normal human IECs promoted cell proliferation and activated glucose metabolism by activating the mTORC1 pathway. Meanwhile, we first found that α-hederin down-regulated glucose metabolism activity and slowed cell proliferation by increasing SNX10 expression in IECs.

Highly expressed SERCA2 triggers tumor cell autophagy and is a druggable vulnerability in triple-negative breast cancer.

Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer (TNBC). Identification of druggable vulnerabilities is an important aim for TNBC therapy. Here, we report that SERCA2 expression correlates with TNBC progression in human patients, which promotes TNBC cell proliferation, migration and chemoresistance. Mechanistically, SERCA2 interacts with LC3B via LIR motif, facilitating WIPI2-independent autophagosome formation to induce autophagy. Autophagy-mediated SERCA2 degradation induces SERCA2 transactivation through a Ca2+/CaMKK/CREB-1 feedback. Moreover, we found that SERCA2-targeting small molecule RL71 enhances SERCA2-LC3B interaction and induces excessive autophagic cell death. The increase in SERCA2 expression predisposes TNBC cells to RL71-induced autophagic cell death in vitro and in vivo. This study elucidates a mechanism by which TNBC cells maintain their high autophagy activity to induce chemoresistance, and suggests increased SERCA2 expression as a druggable vulnerability for TNBC.

Strong and Flexible High-Performance Anion Exchange Membranes with Long-Distance Interconnected Ion Transport Channels for Alkaline Fuel Cells.

Anion exchange membrane fuel cells (AEMFCs), which operate on a variety of green fuels, can achieve high power without emitting greenhouse gases. However, the lack of high ionic conductivity and long-term durability of anion-exchange membranes (AEMs) as their key components is a major obstacle hindering the commercial application of AEMFCs. Here, a series of homogeneous semi-interpenetrating network (semi-IPN) AEMs formed by cross-linking a copolymer of styrene (St) and 4-vinylbenzyl chloride (VBC) with branched polyethylenimine (BPEI) were designed. The pure carbon copolymer skeleton without sulfone/ether bonds accompanied by the semi-IPN endows the AEMs with excellent chemical stability. Moreover, the cross-linking effect of flexible BPEI chains is supposed to promote the "strong-flexible" mechanical properties, while the presence of multiquaternary ammonium groups can boost the formation of microphase separation, thereby enhancing the ionic conductivity of these AEMs. Consequently, the optimized (S1V1)3Q AEM exhibits an excellent hydroxide conductivity of 106 mS cm-1 at 80 °C, as well as more than 81% residual conductivity after soaking in 1 M NaOH at 60 °C for 720 h. Furthermore, the H2/O2 fuel cell assembled with (S1V1)3Q AEM delivers a peak power density of 150.2 mW cm-2 at 60 °C and 40% relative humidity. All results indicate that the approach of combining a pure carbon backbone polymer with a semi-IPN structure may be a viable strategy for fabricating AEMs that can be used in AEMFCs for long-term applications.

Identification of Significant Modules and Targets of Xian-Lian-Jie-Du Decoction Based on the Analysis of Transcriptomics, Proteomics and Single-Cell Transcriptomics in Colorectal Tumor.

Purpose: Colorectal cancer (CRC) remains the third most common tumor worldwide. Ulcerative colitis (UC) could cause chronic inflammation and ulcers in the colon and rectum. UC is a risk factor for a high incidence of CRC, and the incidence of UC-associated CRC (UC-CRC) is still increasing. Chinese medicine prescription, Xian-Lian-Jie-Du decoction (XLJDD), has been proven its efficacy in some UC-CRC patients. However, the mechanism of XLJDD in treating UC-CRC remains unknown. This study aimed to investigate the mechanism of XLJDD in treating UC-CRC. Methods: We constructed an AOM/DSS mouse model that could simulate the various stages of UC-CRC in humans. XLJDD and its 5 main components are used to treat the AOM/DSS model, respectively. With the power of high-throughput sequencing technology, we described the mechanism of XLJDD from transcriptomics, proteomics, and single-cell transcriptomics. Results: Our results showed that XLJDD could effectively suppress the occurrence and development of colorectal tumors. Using the weighted correlation network analysis (WGCNA), several mRNA and protein modules that respond to XLJDD have been identified. Moreover, two essential genes, Mfsd2a and Ccdc85c, were caught our attention. They were prognostic markers in CRC patients, and their expression could be significantly modulated by XLJDD, showing their potential as effective targets of XLJDD. In addition, we also discovered that XLJDD could affect the cell composition of the colorectal tumor environment, especially in the infiltration of B cells. Conclusion: We demonstrated that XLJDD could prevent the initiation and development of colorectal tumors by modulating the expression of Mfsd2a and Ccdc85c and reducing the infiltration of B cells in the tumor microenvironment of colorectal tumor.

Association of frailty and cognitive function disorders in old patients with COVID-19: a protocol of systematic review and meta-analysis.

INTRODUCTION: COVID-19 infections have become an urgent worldwide public health concern. Although it is primarily a respiratory disease, up to two-thirds of hospitalised COVID-19 patients exhibit nervous system damage and an increased risk of frailty. In this study,we aim to investigate the relationship between frailty and cognitive function disorders in patients with COVID-19 with a systematic review and meta-analysis approach. METHODS AND ANALYSIS: This meta-analysis has been registered by the International Prospective Register of Systematic Reviews. We will search for relevant studies from PubMed, Embase, Chinese Biological Medical Database, China National Knowledge Infrastructure, Wanfang Database, the Cochrane Central Register of Controlled Trials databases, from their inception to 5 July 2021. We will also search reference lists of selected articles for additional studies. Our search strategy will have no language restrictions. We will employ a fixed or random-effects model to calculate OR and 95% CIs for pooled data, and assess heterogeneity using Cochrane's Q and I2 tests. The primary outcome will be the rate of cognitive disorders related to frailty in old patients with COVID-19. ETHICS AND DISSEMINATION: Ethical approval is not essential since data will be extracted from previously published studies. The results of this meta-analysis will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021257148.

Single-centre empirical analysis of double-balloon enteroscopy in the diagnosis and treatment of small bowel diseases: A retrospective study of 466 cases.

BACKGROUND AND OBJECTIVE: The diagnosis and treatment of small bowel diseases (SBDs) has always been a challenge. The purpose of this study was to evaluate the value of double-balloon enteroscopy (DBE) in the diagnosis and treatment of small bowel diseases. METHOD: The clinical data of 466 patients who underwent double-balloon enteroscopy (DBE) in the Endoscope Center of Gastroenterology Department of the First People's Hospital of Yunnan Province from Jan. 2015 to Dec. 2020 were analysed retrospectively. The factors included age, sex, indications, endoscopic treatment results, pathological results, discharge diagnosis and so on. RESULTS: A total of 370 patients underwent 466 double-balloon enteroscopies, among whom 274 underwent one examination and 96 received two-way examinations (oral and transanal approaches). Abnormalities were detected in 299 cases, with a detection rate of 80.81% (299/370). The common indications were occult gastrointestinal bleeding (OGIB) (30.8%, 114/370) and abdominal pain (28.3%, 105/370). The diagnosis rates were 64.9% and 77.1%, respectively. The common positive findings included nonspecific inflammation/erosion (60 cases), ulcers (34 cases), diverticulum (32 cases), polyps (26 cases) and Crohn's disease (CD) (24 cases). The common tumours were lymphoma(12 cases), adenocarcinoma(11 cases) and stromal tumour(8 cases). Lymphoma was mostly located in the ileum, while stromal tumours and adenocarcinoma were mostly located in the duodenum and jejunum. The main endoscopic intervention measures were haemostasis and polypectomy, including haemostatic clip, argon plasma coagulation (APC), endoscopic mucosal resection (EMR), endoscopic trap resection, endoscopic foreign body extraction and other operations, without serious complications. CONCLUSION: DBE has a high success rate in the diagnosis and treatment of some SBDs, and it is a safe and effective management method.

HIPK3 Inhibition by Exosomal hsa-miR-101-3p Is Related to Metabolic Reprogramming in Colorectal Cancer.

BACKGROUND: Exosomes are extracellular vesicles secreted by most cells to deliver functional cargoes to recipient cells. MicroRNAs (miRNAs) constitute a significant part of exosomal contents. The ease of diffusion of exosomes renders them speedy and highly efficient vehicles to deliver functional molecules. Cancer cells secrete more exosomes than normal cells. Reports have showed that exosomal miRNAs of cancer cells facilitate cancer progression. Yet the complexity of cancer dictates that many more functional exosomal miRNAs remain to be discovered. METHODS: In this study, we analyzed miRNA expression profiles of tissue and plasma exosome samples collected from 10 colorectal cancer (CRC) patients and 10 healthy individuals. We focused on hsa-miR-101-3p (101-3p), a profoundly up-regulated miRNA enriched in plasma exosomes of patients bearing CRC. We performed target analysis of 101-3p and pursued functional studies of this microRNA in two colorectal cancer cell lines, namely HCT116 and SW480. RESULTS: Our results indicated that inhibiting 101-3p slowed cell growth and retarded cell migration in vivo in two colorectal cancer cell lines. Target analysis showed that Homeodomain-interacting protein kinase (HIPK3) is a target of miR-101-3p. HCT116 and SW480 cells stably overexpressing HIPK3 showed increased level of phosphorylated FADD, as well as retarded cell growth, migration, and increased sensitivity to 5-FU. In-depth analysis revealed increased mitochondrial membrane potential upon HIPK3 overexpression along with increased production of reactive oxygen species, number of mitochondria, and expression of respiratory complexes. Measurements of glycolytic parameters and enzymes revealed decreased level of glycolysis upon HIPK3 overexpression in these two cell lines. Xenograft model further confirmed a profoundly improved potency of the synergistic treatment combining both 5-FU and 101-3p inhibitor compared to 5-FU alone. CONCLUSION: This study unraveled an oncogenic nature of the exosomal 101-3p and suggested a relationship between the 101-3p-HIPK3 axis and metabolic homeostasis in colorectal cancer. Expression level of 101-3p is positively correlated with glycolytic capacity in CRC and therefore 101-3p itself is an oncomiR. Combining 101-3p inhibitor with chemotherapeutic agents is an effective strategy against CRC.

Synthesis and properties of EPDM-based oil-absorptive gels with different types of EPDM and styrene derivatives.

A series of oil gels based on different types of ethylene-propylene-diene (EPDM) and styrene derivatives crosslinked with divinylbenzene (DVB) were synthesized by suspension polymerization. Effects of EPDM types and styrene derivatives on gel fraction, swelling ratio (q), solubility parameter (δ), average molecular weight between cross-links (M c), and oil absorption and oil retention of EPDM-based oil-absorptive gels were studied. Characterization of EPDM-based oil-absorptive gels with different styrene derivatives was performed by Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and oil absorbency tests. The results showed that the double bond of the EPDM side chains was crosslinked with 4-tert-butyl styrene (t-BS), α-methyl styrene (α-MSt), styrene (St) or 4-methyl styrene (4-MSt) to form a three-dimensional network structure, respectively. Compared with the other three EPDM-based oil-absorptive gels, t-BS-EPDM-DVB (ESSB) has the best oil absorption and oil retention, which is mainly due to the fact that the substituent of t-BS is much larger than those of St, 4-MSt and α-MSt. The maximum oil absorption of the ESSB in chloroform was 23 g g-1. This investigation clearly distinguishes the influence of the synthetic raw materials of the EPDM-based oil-absorptive gels on their properties under study, which helps to optimize EPDM-based oil-absorptive materials according to actual applications.

Triggering a switch from basal- to luminal-like breast cancer subtype by the small-molecule diptoindonesin G via induction of GABARAPL1.

Breast cancer is a heterogeneous disease that includes different molecular subtypes. The basal-like subtype has a poor prognosis and a high recurrence rate, whereas the luminal-like subtype confers a more favorable patient prognosis partially due to anti-hormone therapy responsiveness. Here, we demonstrate that diptoindonesin G (Dip G), a natural product, exhibits robust differentiation-inducing activity in basal-like breast cancer cell lines and animal models. Specifically, Dip G treatment caused a partial transcriptome shift from basal to luminal gene expression signatures and prompted sensitization of basal-like breast tumors to tamoxifen therapy. Dip G upregulated the expression of both GABARAPL1 (GABAA receptor-associated protein-like 1) and ERß. We revealed a previously unappreciated role of GABARAPL1 as a regulator in the specification of breast cancer subtypes that is dependent on ERß levels. Our findings shed light on new therapeutic opportunities for basal-like breast cancer via a phenotype switch and indicate that Dip G may serve as a leading compound for the therapy of basal-like breast cancer.

miR-129-5p inhibits proliferation, migration, and invasion in rectal adenocarcinoma cells through targeting E2F7.

microRNAs (miRNAs), a kind of small noncoding RNAs, are considered able to regulate expression of genes and mediate RNA silencing. miR-129-5p was shown to be a cancer-related miRNA. However, the influence of miR-129-5p in rectal adenocarcinoma (READ) development remains to be determined. Based on the TCGA data, downregulation of miR-129-5p in READ samples was observed. Manual restoration of the miR-129-5p in SW1463 and SW480 cell lines significantly inhibited invasion, migration, and proliferation of READ cell lines, while the apoptosis ability was enhanced. Meanwhile, we found E2F7 acted as a potential target of miR-129-5p and was upregulated in READ samples. E2F7 upregulation reversed the repression of miR-129-5p on READ development. Finally, in vivo experiments showed that inhibition of tumor growth in nude mice was achieved through upregulating miR-129-5p. Overall, our findings suggest increasing of miR-129-5p leads to the suppression of READ progression through regulating the expression of E2F7, which may provide novel insights into the treatment of READ.