Low-density polyethylene microplastics and biochar interactively affect greenhouse gas emissions and microbial community structure and function in paddy soil.

Paddy soils are susceptible to microplastics (MPs) contamination. As a common soil amendment, biochar (BC) has been extensively applied in paddy fields. The co-occurrence of MPs and BC may cause interactive effects on soil biogeochemical processes, which has yet been well studied. In this study, a 41-days of microcosm experiment was conducted using paddy soil added with 0.5-1.5 wt% of low-density polyethylene (LDPE) and 5 wt% of BC individually or jointly. Application of BC, LDPE, or their mixture into soil significantly increased the emission of methane (CH4), but suppressed the emission of carbon dioxide (CO2). LDPE addition lowered soil nitrous oxide (N2O) emissions, while BC exerted an opposite effect. Proteobacteria was the most dominant phylum with a relative abundance range of 35.1-51.0%, followed by Actinobacteria (19.3-30.9%) and Acidobacteria (7.5-23.5%). The abundances of the mcrA gene and pH values were increased in soils added with BC or/and LDPE, which were the possible reasons for the higher CH4 emissions in these treatments. The emission of N2O was positively related to the abundances of norB and narG genes, suggesting denitrification was a major pathway to produce N2O. Results of structural equation modeling demonstrated that addition of BC or/and LDPE MPs could affect greenhouse gas emissions from paddy soil by altering soil chemical properties, microbial community structure, and functional gene abundances.

Landscape of NcRNAs involved in drug resistance of breast cancer.

Breast cancer (BC) leads to the most amounts of deaths among women. Chemo-, endocrine-, and targeted therapies are the mainstay drug treatments for BC in the clinic. However, drug resistance is a major obstacle for BC patients, and it leads to poor prognosis. Accumulating evidences suggested that noncoding RNAs (ncRNAs) are intricately linked to a wide range of pathological processes, including drug resistance. Till date, the correlation between drug resistance and ncRNAs is not completely understood in BC. Herein, we comprehensively summarized a dysregulated ncRNAs landscape that promotes or inhibits drug resistance in chemo-, endocrine-, and targeted BC therapies. Our review will pave way for the effective management of drug resistance by targeting oncogenic ncRNAs, which, in turn will promote drug sensitivity of BC in the future.

Unconventional protein post-translational modifications: the helmsmen in breast cancer.

Breast cancer is the most prevalent malignant tumor and a leading cause of mortality among females worldwide. The tumorigenesis and progression of breast cancer involve complex pathophysiological processes, which may be mediated by post-translational modifications (PTMs) of proteins, stimulated by various genes and signaling pathways. Studies into PTMs have long been dominated by the investigation of protein phosphorylation and histone epigenetic modifications. However, with great advances in proteomic techniques, several other PTMs, such as acetylation, glycosylation, sumoylation, methylation, ubiquitination, citrullination, and palmitoylation have been confirmed in breast cancer. Nevertheless, the mechanisms, effects, and inhibitors of these unconventional PTMs (particularly, the non-histone modifications other than phosphorylation) received comparatively little attention. Therefore, in this review, we illustrate the functions of these PTMs and highlight their impact on the oncogenesis and progression of breast cancer. Identification of novel potential therapeutic drugs targeting PTMs and development of biological markers for the detection of breast cancer would be significantly valuable for the efficient selection of therapeutic regimens and prediction of disease prognosis in patients with breast cancer.

Long noncoding RNA SNHG1 promotes TERT expression by sponging miR-18b-5p in breast cancer.

BACKGROUND: Long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) plays a positive role in the progression of human malignant tumors. However, the molecular mechanism of SNHG1 remains elusive in breast cancer. RESULTS: LncRNA SNHG1 was upregulated and had a positive relationship with poor prognosis according to bioinformatics analysis in pan-cancer including breast cancer. Silencing SNHG1 inhibited tumorigenesis in breast cancer both in vitro and in vivo. Mechanistically, SNHG1 functioned as a competing endogenous RNA (ceRNA) to promote TERT expression by sponging miR-18b-5p in breast cancer. miR-18b-5p acted as a tumor repressor in breast cancer. Moreover, the combination of SNHG1 knockdown and TERT inhibitor administration showed a synergistic inhibitory effect on breast cancer growth in vivo. Finally, E2F1 as a transcription factor, binding to SNHG1 promoter and enhanced SNHG1 transcription in breast cancer. CONCLUSIONS: Our results provide a comprehensive understanding of the oncogenic mechanism of lncRNA SNHG1 in breast cancer. Importantly, we identified a novel E2F1-SNHG1-miR-18b-5p-TERT axis, which may be a potential therapeutic target for breast cancer. Our results also provided a potential treatment for breast cancer when knockdown SNHG1 and TERT inhibitor administration simultaneously.

LncRNA TINCR favors tumorigenesis via STAT3-TINCR-EGFR-feedback loop by recruiting DNMT1 and acting as a competing endogenous RNA in human breast cancer.

The long noncoding RNA (lncRNA) TINCR has recently been found to be associated with the progression of human malignancies, but the molecular mechanism of TINCR action remains elusive, particularly in breast cancer. The oncogenic role of TINCR was examined in vitro and in vivo in breast cancer. Next, the interaction between TINCR, DNMT1, and miR-503-5p methylation was explored. Moreover, the mechanism by which TINCR enhances EGFR expression and downstream signaling via an RNA-RNA interaction was comprehensively investigated. Furthermore, upstream transcriptional regulation of TINCR expression by STAT3 was examined by performing chromatin immunoprecipitation. Finally, feedback signaling in the STAT3-TINCR-EGFR downstream cascade was also investigated. TINCR is upregulated in human breast cancer tissues, and TINCR knockdown suppresses tumorigenesis in vitro and in vivo. Mechanistically, TINCR recruits DNMT1 to the miR-503-5p locus promoter, which increases the methylation and suppresses the transcriptional expression of miR-503-5p. Furthermore, TINCR also functions as a competing endogenous RNA to upregulate EGFR expression by sponging miR-503-5p. In addition, TINCR stimulates JAK2-STAT3 signaling downstream from EGFR, and STAT3 reciprocally enhances the transcriptional expression of TINCR. Our findings broaden the current understanding of the diverse manners in which TINCR functions in cancer biology. The newly identified STAT3-TINCR-EGFR-feedback loop could serve as a potential therapeutic target for human cancer.

Identification of long-term survival-associated gene in breast cancer.

Breast cancer patients at the same stage may show different clinical prognoses or different therapeutic effects of systemic therapy. Differentially expressed genes of breast cancer were identified from GSE42568. Through survival, receiver operating characteristic (ROC) curve, random forest, GSVA and a Cox regression model analyses, genes were identified that could be associated with survival time in breast cancer. The molecular mechanism was identified by enrichment, GSEA, methylation and SNV analyses. Then, the expression of a key gene was verified by the TCGA dataset and RT-qPCR, Western blot, and immunohistochemistry. We identified 784 genes related to the 5-year overall survival time of breast cancer. Through ROC curve and random forest analysis, 10 prognostic genes were screened. These were integrated into a complex by GSVA, and high expression of the complex significantly promoted the recurrence-free survival of patients. In addition, key genes were related to immune and metabolic-related functions. Importantly, we identified methylation of MEX3A and TBC1D 9 and mutations events. Finally, the expression of UGCG was verified by the TCGA dataset and by experimental methods in our own samples. These results indicate that 10 genes may be potential biomarkers and therapeutic targets for long-term survival in breast cancer, especially UGCG.

Noncoding RNAs: the shot callers in tumor immune escape.

Immunotherapy, designed to exploit the functions of the host immune system against tumors, has shown considerable potential against several malignancies. However, the utility of immunotherapy is heavily limited due to the low response rate and various side effects in the clinical setting. Immune escape of tumor cells may be a critical reason for such low response rates. Noncoding RNAs (ncRNAs) have been identified as key regulatory factors in tumors and the immune system. Consequently, ncRNAs show promise as targets to improve the efficacy of immunotherapy in tumors. However, the relationship between ncRNAs and tumor immune escape (TIE) has not yet been comprehensively summarized. In this review, we provide a detailed account of the current knowledge on ncRNAs associated with TIE and their potential roles in tumor growth and survival mechanisms. This review bridges the gap between ncRNAs and TIE and broadens our understanding of their relationship, providing new insights and strategies to improve immunotherapy response rates by specifically targeting the ncRNAs involved in TIE.

Long Noncoding RNAs Control the Modulation of Immune Checkpoint Molecules in Cancer.

Long noncoding RNAs (lncRNA) that are associated with immune checkpoints have not been identified, and the mechanism by which such lncRNAs might regulate the expression of immune checkpoints is unknown in human cancer. Immune checkpoint-associated lncRNAs (ICP-lncRNA) were identified and validated via a comprehensive bioinformatic analysis of The Cancer Genome Atlas data. These ICP-lncRNAs were involved in key immune response and immune cell receptor signaling pathways. The expression of ICP-lncRNAs was upregulated and correlated with a poor prognosis in patients with cancer. HLA complex P5 (HCP5) and myocardial infarction associated transcript (MIAT) promoted tumor growth and upregulated the expression of PD-L1/CD274 via a competing endogenous RNA mechanism of sponging miR-150-5p. The combination of MIAT knockdown and PD-L1 antibody administration showed a synergistic inhibitory effect on tumor growth. Finally, the expression of both HCP5 and MIAT was confirmed to be transcriptionally suppressed by CCCTC-binding factor (CTCF), and lipopolysaccharide induced CTCF eviction from the HCP5 and MIAT promoters, attenuating the transcriptionally suppressive activity of CTCF. This study enlarges the functional landscape of known lncRNAs in human cancer and indicates novel insights into their roles in the field of tumor immunity and immunotherapy. These findings may aid in the comprehensive management of human cancer with immunotherapy.

Enhanced NK cell adoptive antitumor effects against breast cancer in vitro via blockade of the transforming growth factor-ß signaling pathway.

Natural killer (NK) cells have great potential for improving cancer immunotherapy. Adoptive NK cell transfer, an adoptive immunotherapy, represents a promising nontoxic anticancer therapy. However, existing data indicate that tumor cells can effectively escape NK cell-mediated apoptosis through immunosuppressive effects in the tumor microenvironment, and the therapeutic activity of adoptive NK cell transfer is not as efficient as anticipated. Transforming growth factor-beta (TGF-ß) is a potent immunosuppressant. Genetic and epigenetic events that occur during mammary tumorigenesis circumvent the tumor-suppressing activity of TGF-ß, thereby permitting late-stage breast cancer cells to acquire an invasive and metastatic phenotype in response to TGF-ß. To block the TGF-ß signaling pathway, NK cells were genetically modified with a dominant-negative TGF-ß type II receptor by optimizing electroporation using the Amaxa Nucleofector system. These genetically modified NK cells were insensitive to TGF-ß and resisted the suppressive effect of TGF-ß on MCF-7 breast cancer cells in vitro. Our results demonstrate that blocking the TGF-ß signaling pathway to modulate the tumor microenvironment can improve the antitumor activity of adoptive NK cells in vitro, thereby providing a new rationale for the treatment of breast cancer.