NcRNA Regulated Pyroptosis in Liver Diseases and Traditional Chinese Medicine Intervention: A Narrative Review.

Pyroptosis is a novel pro-inflammatory mode of programmed cell death that differs from ferroptosis, necrosis, and apoptosis in terms of its onset and regulatory mechanisms. Pyroptosis is dependent on cysteine aspartate protein hydrolase (caspase)-mediated activation of GSDMD, NLRP3, and the release of pro-inflammatory cytokines, interleukin-1 (IL-1ß), and interleukin-18 (IL-18), ultimately leading to cell death. Non-coding RNA (ncRNA) is a type of RNA that does not encode proteins in gene transcription but plays an important regulatory role in other post-transcriptional links. NcRNA mediates pyroptosis by regulating various related pyroptosis factors, which we termed the pyroptosis signaling pathway. Previous researches have manifested that pyroptosis is closely related to the development of liver diseases, and is essential for liver injury, alcoholic fatty liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and liver cancer. In this review, we attempt to address the role of the ncRNA-mediated pyroptosis pathway in the above liver diseases and their pathogenesis in recent years, and briefly outline that TCM (Traditional Chinese Medicine) intervene in liver diseases by modulating ncRNA-mediated pyroptosis, which will provide a strategy to find new therapeutic targets for the prevention and treatment of liver diseases in the future.

Construction of a highly efficient adsorbent for one-step purification of recombinant proteins: Functionalized cellulose-based monolith fabricated via phase separation method.

Currently, purification step in the recombinant protein manufacture is still a great challenge and its cost far outweighs those of the upstream process. In this study, a functionalized cellulose-based monolith was constructed as an efficient affinity adsorbent for one-step purification of recombinant proteins. Firstly, the fundamental cellulose monolith (CE monolith) was fabricated based on thermally induced phase separation, followed by being modified with nitrilotriacetic acid anhydride through esterification to give NCE monolith. After chelating with Ni2+, the affinity adsorbent NCE-Ni2+ monolith was obtained, which was demonstrated to possess a hierarchically porous morphology with a relatively high surface area, porosity and compressive strength. The adsorption behavior of NCE-Ni2+ monolith towards ß2-microglobulin with 6 N-terminus His-tag (His-ß2M) was evaluated through batch and fixed-bed column experiments. The results revealed that NCE-Ni2+ monolith exhibited a relatively fast His-ß2M adsorption rate with a maximum adsorption capacity of 329.2 mg/g. The fixed-bed column adsorption implied that NCE-Ni2+ monolith showed high efficiency for His-ß2M adsorption. Finally, NCE-Ni2+ monolith was demonstrated to have an excellent His-ß2M purification ability from E. coli lysate with exceptional reusability. Therefore, the resultant NCE-Ni2+ monolith had large potential to be used as an efficient adsorbent for recombinant protein purification in practical applications.

The ω-3 polyunsaturated fatty acid docosahexaenoic acid enhances NK-cell antitumor effector functions.

ω-3 polyunsaturated fatty acids (PUFAs) are known to directly repress tumour development and progression. In this study, we explored whether docosahexaenoic acid (DHA), a type of ω-3 PUFA, had an immunomodulatory role in promoting tumour growth in immunocompetent mice. The number of natural killer (NK) cells but not the number of T or B cells was decreased by DHA supplementation in various tissues under physiological conditions. Although the frequency and number of NK cells were comparable, IFN-γ production by NK cells in both the spleen and lung was increased in DHA-supplemented mice in the mouse B16F10 melanoma tumour model. Single-cell RNA sequencing (scRNA-seq) revealed that DHA promoted effector function and oxidative phosphorylation in NK cells but had no obvious effects on other immune cells. Using Rag2-/- mice and NK-cell depletion by PK136 antibody injection, we demonstrated that the suppression of B16F10 melanoma tumour growth in the lung by DHA supplementation was dependent mainly on NK cells. In vitro experiments showed that DHA directly enhanced IFN-γ production, CD107a expression and mitochondrial oxidative phosphorylation (OXPHOS) activity, and slightly increased proliferator-activated receptor gamma coactivator-1α (PGC-1α) protein expression in NK cells. The PGC-1α inhibitor SR-18292 in vitro and NK cell-specific knockout of PGC-1α in mice reversed the antitumour effects of DHA. In summary, our findings broaden the current knowledge on how DHA supplementation protects against cancer growth from the perspective of immunomodulation by upregulating PGC-1α signalling-mediated mitochondrial OXPHOS activity in NK cells.

Transgenerational effects of extracts containing Microcystin-LR exposure on reproductive toxicity and offspring growth inhibition in a model organism zebrafish.

Cyanobacteria cell lysates release numerous toxic substances (e.g., cyanotoxins) into the water, posing a serious threat to human health and aquatic ecosystems. Microcystins (MCs) are among the most abundant cyanotoxins in the cell lysates, with microcystin-LR (MC-LR) being one of the most common and highly toxic congeners. In this study, zebrafish (Danio rerio) were exposed to different levels MC-LR that from extracts of Microcystis aeruginosa. Changes in the MC-LR accumulations, organ coefficients, and antioxidant enzyme activities in the zebrafish were analyzed. Transgenerational reproductive toxicity of MC-LR in the maternal and paternal generations was further investigated, as well as the influences of extracts containing MC-LR exposures of the F1 on the growth of zebrafish. The study found that high levels of MC-LR could be detected in the major organs of adult zebrafish, particularly in spleen. Notably, concentration of MC-LR in the spermary was significantly higher than that in the ovarium. MC-LR could induce oxidative damage by affecting the activities of catalase and superoxide dismutase. Inherited from F0, MC-LR led to impaired development in the F1 generation. Difference in offspring survival rates could be observed in the groups with different MC-LR levels of maternal and paternal exposures. This study reveals transgenerational effects of MC-LR on the reproductive toxicity and offspring growth inhibition to the aquatic organisms, which should be emphasized in the future ecological risk assessment.

Single-cell landscape of the cellular microenvironment in three different colonic polyp subtypes in children.

BACKGROUND: The understanding of the heterogeneous cellular microenvironment of colonic polyps in paediatric patients with solitary juvenile polyps (SJPs), polyposis syndrome (PJS) and Peutz-Jeghers syndrome (PJS) remains limited. METHODS: We conducted single-cell RNA sequencing and multiplexed immunohistochemistry (mIHC) analyses on both normal colonic tissue and different types of colonic polyps obtained from paediatric patients. RESULTS: We identified both shared and disease-specific cell subsets and expression patterns that played important roles in shaping the unique cellular microenvironments observed in each polyp subtype. As such, increased myeloid, endothelial and epithelial cells were the most prominent features of SJP, JPS and PJS polyps, respectively. Noticeably, memory B cells were increased, and a cluster of epithelial-mesenchymal transition (EMT)-like colonocytes existed across all polyp subtypes. Abundant neutrophil infiltration was observed in SJP polyps, while CX3CR1hi CD8+ T cells and regulatory T cells (Tregs) were predominant in SJP and JPS polyps, while GZMAhi natural killer T cells were predominant in PJS polyps. Compared with normal colonic tissues, myeloid cells exhibited specific induction of genes involved in chemotaxis and interferon-related pathways in SJP polyps, whereas fibroblasts in JPS polyps had upregulation of myofiber-associated genes and epithelial cells in PJS polyps exhibited induction of a series of nutrient absorption-related genes. In addition, the TNF-α response was uniformly upregulated in most cell subsets across all polyp subtypes, while endothelial cells and fibroblasts separately showed upregulated cell adhesion and EMT signalling in SJP and JPS polyps. Cell-cell interaction network analysis showed markedly enhanced intercellular communication, such as TNF, VEGF, CXCL and collagen signalling networks, among most cell subsets in polyps, especially SJP and JPS polyps. CONCLUSION: These findings strengthen our understanding of the heterogeneous cellular microenvironment of polyp subtypes and identify potential therapeutic approaches to reduce the recurrence of polyps in children.

mTORC2 acts as a gatekeeper for mTORC1 deficiency-mediated impairments in ILC3 development.

Group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function. Recent studies have investigated the role of the mammalian target of rapamycin complex (mTOR) in ILC3s, whereas the mTORC1-related mechanisms and crosstalk between mTORC1 and mTORC2 involved in regulating ILC3 homeostasis remain unknown. In this study, we found that mTORC1 but not mTORC2 was critical in ILC3 development, IL-22 production, and ILC3-mediated intestinal homeostasis. Single-cell RNA sequencing revealed that mTORC1 deficiency led to disruption of ILC3 heterogeneity, showing an increase in differentiation into ILC1-like phenotypes. Mechanistically, mTORC1 deficiency decreased the expression of NFIL3, which is a critical transcription factor responsible for ILC3 development. The activities of both mTORC1 and mTORC2 were increased in wild-type ILC3s after activation by IL-23, whereas inhibition of mTORC1 by Raptor deletion or rapamycin treatment resulted in increased mTORC2 activity. Previous studies have demonstrated that S6K, the main downstream target of mTORC1, can directly phosphorylate Rictor to dampen mTORC2 activity. Our data found that inhibition of mTORC1 activity by rapamycin reduced Rictor phosphorylation in ILC3s. Reversing the increased mTORC2 activity via heterozygous or homozygous knockout of Rictor in Raptor-deleted ILC3s resulted in severe ILC3 loss and complete susceptibility to intestinal infection in mice with mTORC1 deficiency (100% mortality). Thus, mTORC1 acts as a rheostat of ILC3 heterogeneity, and mTORC2 protects ILC3s from severe loss of cells and immune activity against intestinal infection when mTORC1 activity is diminished.

Tuber indicum and T. lijiangense colonization differentially regulates plant physiological responses and mycorrhizosphere bacterial community of Castanopsis rockii seedlings.

Black truffles and white truffles are widely studied around the world, but their effects on plant growth and physiological responses, and on the mycorrhizosphere bacterial community of the host plant remain unclear. Here, mycorrhizal colonization of Castanopsis rockii by Tuber indicum (Chinese black truffle) and T. lijiangense (Chinese white truffle), respectively, was induced in a greenhouse study, and their effects on host growth, physiological responses and mycorrhizosphere bacterial communities were compared. The results show that colonization of both Tuber species significantly increased leaf photosynthetic rate, leaf P concentration and mycorrhizosphere acid phosphatase activity, as well as richness of mycorrhizosphere bacterial communities of C. rockii seedlings. However, T. indicum colonization on the one hand significantly decreased tartrate content, bacterial acid phosphatase, phoC gene abundance in the mycorrhizosphere, and peroxidase (POD) activity of ectomycorrhizal root tips, but on the other hand increased mycorrhizosphere pH and superoxide dismutase (SOD) of ectomycorrhizal root tips, compared to T. lijiangense colonization. Moreover, principal coordinate and ß-diversity analyses show significant differences in mycorrhizosphere bacterial community composition between T. indicum and T. lijiangese colonized C. rockii seedlings. Finally, the relative abundance of the bacterium Agromyces cerinus significantly correlated to mycorrhizosphere acid phosphatase activity and leaf P concentration, suggesting that this bacterium might play an important role in P mobilization and acquisition. Overall, these results suggest that T. indicum and T. lijiangense differently regulate their host plant's physiological responses and mycorrhizosphere bacterial community.

METTL3 promotes colorectal cancer metastasis by promoting the maturation of pri-microRNA-196b.

PURPOSE: Methyltransferase-like 3 (METTL3), a key member of the m6A methyltransferase complex, is upregulated in multiple human malignancies and plays a role in regulating tumor migration. This study aimed to reveal the underlying mechanism by which METTL3 in regulates the metastasis of colorectal cancer (CRC). METHODS: We compared METTL3 expression levels in CRC tumor tissues and adjacent nontumor tissues by immunohistochemistry (IHC). The functional roles of METTL3 in CRC were assessed by real-time cell migration assays, wound-healing assays and Transwell assays. miRNA sequencing (miRNA-seq), RNA-binding protein immunoprecipitation (RIP) assays and N6-methyladenosine immunoprecipitation (MeRIP) assays were performed to confirm the molecular mechanism underlying the involvement of METTL3 in CRC cell metastasis. RESULTS: We found that METTL3 was overexpressed in CRC tissues. METTL3 knockdown significantly inhibited CRC cell migration and invasion, while METTL3 overexpression had the opposite effects. Furthermore, we demonstrated that METTL3 regulates miR-196b expression via an N6-methyladenosine (m6A)-pri-miR-196b-dependent mechanism and thereby promotes CRC metastasis. CONCLUSION: This study shows the important role of METTL3 in CRC metastasis and provides novel insight into m6A modification in CRC metastasis.

Phylogenetic Analyses of Hydnobolites and New Species from China.

Hydnobolites is an ectomycorrhizal fungal genus with hypogeous ascomata in the family Pezizaceae (Pezizales). Molecular analyses of Hydnobolites using both single (ITS) and concatenated gene datasets (ITS-nLSU) showed a total of 223 sequences, including 92 newly gained sequences from Chinese specimens. Phylogenetic results based on these two datasets revealed seven distinct phylogenetic clades. Among them, the ITS phylogenetic tree confirmed the presence of at least 42 phylogenetic species in Hydnobolites. Combined the morphological observations with molecular analyses, five new species of Hydnobolites translucidus sp. nov., H. subrufus sp. nov., H. lini sp. nov., H. sichuanensis sp. nov. and H. tenuiperidius sp. nov., and one new record species of H. cerebriformis Tul., were illustrated from Southwest China. Macro- and micro-morphological analyses of ascomata revealed a few, but diagnostic differences between the H. cerebriformis complex, while the similarities of the ITS sequences ranged from 94.4 to 97.2% resulting in well-supported clades.

Ectomycorrhizal synthesis between two Tuber species and six tree species: are different host-fungus combinations having dissimilar impacts on host plant growth?

Truffle cultivation has drawn more and more attention for its high economic and ecological values in the world. To select symbionts suitable for cultivation purposes, we conducted greenhouse-based mycorrhization trials of two Tuber species (T. formosanum and T. pseudohimalayense) with five broad-leaved tree species (Corylus yunnanensis, Quercus aliena var. acutiserrata, Q. acutissima, Q. robur, Q. variabilis) and one conifer species (Pinus armandii). Axenically germinated seedlings of all tree species were either inoculated, or not, with spore suspensions of these two truffles in the greenhouse. Eight months after inoculation, T. formosanum or T. pseudohimalayense ectomycorrhizae were successfully formed on these six tree species, as evidenced by both morphological and molecular analyses. All selected trees showed good receptivity to mycorrhization by both fungi, with average colonization rates visually estimated at 40-50%. Plant growth, photosynthesis, and nutrient uptake were assessed 2 years after inoculation and were mainly affected by host species. Mycorrhization by both fungi significantly improved P uptake of the hosts, and the interaction between truffle species and host plant species had significant effects on leaf water and leaf K concentrations. In addition, a significantly negative correlation between leaf Ca and leaf C concentration was found across all the seedlings. In addition, mycorrhization had slightly increased plant stem and canopy, but had no significant effects on plant photosynthesis. Overall, these results suggest that the effects of these two Tuber ECMF on plant growth and nutrient acquisition depend on the identity of the host species. Moreover, all selected plant species could be symbiotic partners with either T. pseudohimalayense or T. formosanum for field cultivation purposes.

The Ultrahigh Adsorption Capacity and Excellent Photocatalytic Degradation Activity of Mesoporous CuO with Novel Architecture.

In this paper, mesoporous CuO with a novel architecture was synthesized through a conventional hydrothermal approach followed by a facile sintering procedure. HR-TEM analysis found that mesoporous CuO with an interconnected pore structure has exposed high-energy crystal planes of (002) and (200). Theoretical calculations indicated that the high-energy crystal planes have superior adsorption capacity for H+ ions, which is critical for the excellent adsorption and remarkable photocatalytic activity of the anionic dye. The adsorption capacity of CuO to methyl orange (MO) at 0.4 g/L was approximately 30% under adsorption equilibrium conditions. We propose a state-changing mechanism to analyze the synergy and mutual restraint relation among the catalyst CuO, H+ ions, dye and H2O2. According to this mechanism, the degradation rate of MO can be elevated 3.5 times only by regulating the MO ratio in three states.

METTL3 Promotes Esophageal Squamous Cell Carcinoma Metastasis Through Enhancing GLS2 Expression.

Recent studies have identified pleiotropic roles of methyltransferase-like 3 (METTL3) in tumor progression. However, the roles of METTL3 in esophageal squamous cell carcinoma (ESCC) are still unclear. Here, we investigated the function and mechanism of METTL3 in ESCC tumorigenesis. We reported that higher METTL3 expression was found in ESCC tissues and was markedly associated with depth of invasion and poor prognosis. Loss- and gain-of function studies showed that METTL3 promoted the migration and invasion of ESCC cells in vitro. Integrated methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq) analysis first demonstrated that glutaminase 2 (GLS2) was regulated by METTL3 via m6A modification. Our findings identified METTL3/GLS2 signaling as a potential therapeutic target in antimetastatic strategies against ESCC.

Fractional calculus with exponential memory.

The standard definition of the Riemann-Liouville integral is revisited. A new fractional integral is proposed with an exponential kernel. Furthermore, some useful properties such as composition relationship of the new fractional integral and Leibniz integral law are provided. Exact solutions of the fractional homogeneous equation and the non-homogeneous equations are given, respectively. Finally, a finite difference scheme is proposed for solving fractional nonlinear differential equations with exponential memory. The results show the efficiency and convenience of the new fractional derivative.

EF24 induces ferroptosis in osteosarcoma cells through HMOX1.

PURPOSE: EF24, a synthetic analogue of curcumin, was developed as an anti-tumor compound to induce apoptosis, inhibit proliferation and metastasis in various cancers. However, whether EF24 induces ferroptosis in osteosarcoma cells or not, and its underlying mechanism remains largely elusive. METHODS: After EF24 combining with or without other compounds treatments, mRNA expression profiles were proceeded by RNA sequencing. Cytotoxicity was measured by cell counting kit-8 assay. Cell death was quantified by flow cytometer. Gene expression was quantified by real-time PCR. Protein level was detected by western blot. Malonydialdehyde (MDA) level was measured by lipid peroxidation MDA assay kit. Reactive oxygen species (ROS) level was measured by ROS Assay Kit. Ferric ion was measured by Iron Assay kit. RESULTS: EF24 significantly induced cell death in osteosarcoma cell lines, and this effect was significantly reversed by ferrostatin-1, but not Z-VAD(Ome)-FMK, MRT68921 or necrosulfonamide. EF24 significantly increased MDA level, ROS level and intracellular ferric ion level, these effects were significantly attenuated by ferrostatin-1. EF24 upregulated HMOX1 expression in a dose dependent manner, overexpression of HMOX1 facilitated EF24 to induce ferroptosis in osteosarcoma cell lines. HMOX1 knockdown attenuated EF24-induced cytotoxicity and attenuated EF24-induced inhibition of Glutathione Peroxidase 4 (GPX4) expression. CONCLUSION: Our results showed that EF24 upregulated HMOX1 to suppress GPX4 expression to induce ferroptosis by increasing MDA level, ROS level and intracellular ferric ion level. Thus, EF24 might serve as a potential agent for the treatment of HMOX1-positive osteosarcoma patients.

Mycorrhizal synthesis of Tuber pseudohimalayense with seven broad-leaved trees and Pinus armandii.

Truffle cultivation is successfully applied throughout the world for several truffles of European origin. However, just two Chinese black truffles (Tuber indicum and T. himalayense) have been cultivated with a favorable outcome so far. Tuber pseudohimalayense is a black truffle of significant economic relevance in China, but little is known about its mycorrhizal ecology and it is not cultivated in orchards yet. Here, we selected seven broad-leaved tree species (Quercus fabrei, Q. aliena, Castanea mollissima, Carya illinoinensis, Q. glauca, Castanopsis orthacantha, Betula costata), and one coniferous tree (Pinus armandii), and inoculated them with T. pseudohimalayense spore suspension using axenically germinated seedlings under greenhouse conditions. The obtained mycorrhizae, well-developed, were analyzed from the morpho-anatomical and molecular points of view, and their main characteristics described. Synthesized T. pseudohimalayense mycorrhizae showed similar characters on all tree species, with a typical interlocking pseudoparenchymatous mantle and Hartig net, swollen appearance, yellow-brownish color, and long hyaline emanating hyphae with right-angle ramifications. These features are similar to those reported for mycorrhizae formed by related black truffle species. The successful mycorrhizal synthesis of T. pseudohimalayense on multiple trees species indicates that it has potential for cultivation in China.

Circular RNA GLIS2 promotes colorectal cancer cell motility via activation of the NF-κB pathway.

Circular RNAs (circRNAs) are a newly discovered type of biological molecule that belongs to the noncoding RNA family. Abundant evidence has shown that circRNAs are involved in the progression of various cancers. However, the particular functions of circRNAs in colorectal cancer (CRC) remain elusive. In this study, we investigated the differentially expressed circRNAs in three pairs of cancer tissue and adjacent normal tissue of CRC. We revealed that circGLIS2 expression was higher in CRC tissue and cell lines. Gain-and-loss function assays showed that circGLIS2 was involved in the regulation of cell migration. Moreover, overexpressing circGLIS2 in CRC cells activated the NF-κB pathway and induced pro-inflammatory chemokine production, which evoked tumor-associated inflammation through recruiting leukocytes. In turn, when the cancer cells were exposed to the supernatant of circGLIS2 overexpressed cancer cells, they were endowed with the ability of migration and chemokines production. Furthermore, the rescue assay confirmed that circGLIS2 activated NF-κB signaling and promoted cell migration by sponging miR-671. Overall, our study reveals that circGLIS2, acting as a potential oncogene, maintains the abnormal activation state of the NF-κB signaling pathway via the miR-671 sponge mechanism in CRC cells. This study provides a scientific basis for targeting circGLIS2 in colorectal cancer interventions.

Toosendanin-induced apoptosis in colorectal cancer cells is associated with the κ-opioid receptor/ß-catenin signaling axis.

Developing new drugs for killing colorectal cancer (CRC) cells is urgently needed. Here, we explored the antitumor effects of toosendanin (TSN) in CRC, as well as explored its antitumor mechanisms and direct targets. Cell proliferation and apoptosis were analyzed by CCK8, colony formation, real-time cell impedance and flow cytometry. The signaling pathway and Wnt activity were analyzed by Wnt luciferase activity assay, quantitative real-time PCR and western blot. The interaction between TSN and the κ-opioid receptor was analyzed by a molecular docking simulation. BALB/c nude mice were used to detect the effects of TSN on tumor growth in vivo. We found that TSN inhibited proliferation, induced G1 phase arrest and caused caspase-dependent apoptosis in both 5-FU-sensitive and 5-FU-resistant CRC cells. Moreover, TSN effectively inhibited CRC growth in vivo. In terms of the mechanism, TSN inhibited Wnt/ß-catenin signaling in CRC cells, and the molecular docking results showed that TSN could bind to κ-opioid receptors directly. Additionally, TSN-induced apoptosis and ß-catenin decline were both reversed by the selective κ-opioid receptor agonist U50,488H. Our data demonstrate that TSN-induced apoptosis in CRC cells is associated with the κ-opioid receptor/ß-catenin signaling axis, and TSN has promising potential as an antitumor agent for CRC treatment.

The European delicacy Tuber melanosporum forms mycorrhizae with some indigenous Chinese Quercus species and promotes growth of the oak seedlings.

We aimed to test whether Tuber melanosporum and native Chinese oak species could form stable mycorrhizal symbioses. Six oak species were all either inoculated or not, with spores of the Périgord black truffle in the greenhouse. Ectomycorrhizal development was monitored for up to 32 months. Seedling growth was assessed 2 years after inoculation. From 6 months after inoculation, Tuber melanosporum ectomycorrhizae were successfully produced on five Quercus species endemic to China, as shown by morphological, anatomical, and molecular analyses. Quercus mongolica and Q. longispica showed high receptivity to mycorrhization by T. melanosporum. The symbioses obtained with these two species and with Quercus senescens were stable for at least 32 months. Averaged over all three oak species, mycorrhization by T. melanosporum significantly enhanced canopy diameter, number of leaves, and mean leaf dimension. In spring 2019, mycorrhization by T. melanosporum accelerated budbreak in Q. mongolica. Quercus fabrei and Q. variabilis formed ectomycorrhizae up to 9 months after inoculation but seedlings died 3 months later, probably because of damage by grazing insects. Quercus pseudosemecarpifolia failed to form ectomycorrhizae. Results suggest that T. melanosporum-mycorrhized Q. mongolica and Q. longispica seedlings could be tested for ascocarp production and increased performance in the field.

MiR-27b-3p promotes migration and invasion in colorectal cancer cells by targeting HOXA10.

PURPOSE: Dysregulation of microRNAs (miRNAs) contributes to tumor progression via the regulation of the expression of specific oncogenes and tumor suppressor genes. One such example, miR-27b-3p, has reportedly been involved in tumor progression in many types of cancer. The aim of the present study was to delve into the role and the underlying mechanism of miR-27b-3p in colorectal cancer (CRC) cells. METHODS: In the present study, we detected the expression level of miR-27b-3p by RT-PCR. The effect of miR-27b-3p overexpression on cell proliferation in CRC cells was evaluated by cell counting and Edu assays. Transwell migration and invasion assays were used to examine the effects of cell migration and invasion. Bioinformatics, luciferase reporter assay and western blot assay were performed to identify the target of miR-27b-3p. RESULTS: Here, we have demonstrated that although miR-27b-3p can affect cell morphology, it has no observable effect on the proliferation of CRC cells. However, it significantly promotes the migration and invasion of CRC cells. We discovered that HOXA10 was a newly identified target of miR-27b-3p in CRC cells, as confirmed by bioinformatics, western blots and dual luciferase reporter assay. Furthermore, the overexpression of miR-27b-3p or the suppression of HOXA10 can activate the integrin ß1 signaling pathway. In conclusion, our results reveal a new function of miR-27b-3p that demonstrates its ability to promote CRC cell migration and invasion by targeting the HOXA10/integrin ß1 cell signal axis. CONCLUSION: This may provide a mechanism to explain why miR-27b-3p promotes CRC cell migration and invasion.

ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin.

Novel drugs are urgently needed for gastric cancer (GC) treatment. The thioredoxin-thioredoxin reductase (TRX-TRXR) system has been found to play a critical role in GC tumorigenesis and progression. Thus, agents that target the TRX-TRXR system may be highly efficacious as GC treatments. In this study, we showed that chaetocin, a natural product isolated from the Chaetomium species of fungi, inhibited proliferation, induced G2/M phase arrest and caspase-dependent apoptosis in both in vitro and in vivo models (cell xenografts and patient-derived xenografts) of GC. Chaetocin inactivated TRXR-1, resulting in the accumulation of reactive oxygen species (ROS) in GC cells; overexpression of TRX-1 as well as cotreatment of GC cells with the ROS scavenger N-acetyl-L-cysteine attenuated chaetocin-induced apoptosis; chaetocin-induced apoptosis was significantly increased when GC cells were cotreated with auranofin. Moreover, chaetocin was shown to inactivate the PI3K/AKT pathway by inducing ROS generation; AKT-1 overexpression also attenuated chaetocin-induced apoptosis. Taken together, these results reveal that chaetocin induces the excessive accumulation of ROS via inhibition of TRXR-1. This is followed by PI3K/AKT pathway inactivation, which ultimately inhibits proliferation and induces caspase-dependent apoptosis in GC cells. Chaetocin therefore may be a potential agent for GC treatment.