RNA modifications are diverse post-transcriptional modifications that regulate RNA metabolism and gene expression. RNA modifications, and the writers, erasers, and readers that catalyze these ...modifications, serve as important signaling machineries in cellular stress responses and disease pathogenesis. In response to stress, RNA modifications are mobilized to activate or inhibit the signaling pathways that combat stresses, including oxidative stress, hypoxia, therapeutic stress, metabolic stress, heat shock, DNA damage, and ER stress. The role of RNA modifications in response to these cellular stressors is context- and cell-type-dependent. Due to their pervasive roles in cell biology, RNA modifications have been implicated in the pathogenesis of different diseases, including cancer, neurologic and developmental disorders and diseases, and metabolic diseases. In this review, we aim to summarize the roles of RNA modifications in molecular and cellular stress responses and diseases.
Excessive, high doses of ultraviolet B (UVB) UVB irradiation are known to cause skin cancer, aging and immunosuppression. On the contrary, moderate low doses of UVB irradiation are shown to be ...essential and beneficial to human health, including a tumor‐suppressive effect. However, the mechanism by which low levels of UVB suppress tumorigenesis remains unclear. Here, using tumor‐bearing mouse models, we show that moderate low repetitive UVB irradiation increases the percentage of activated CD4+ and CD8+ T cells, and CD103+ conventional type 1 dendritic cells (cDC1s), while it decreases the number of immunosuppressive, M2‐like macrophages in the tumors. Finally, in mice, deletion of Batf3, a transcription factor critical for the development of conventional dendritic cells, including the CD103+ cDC1s, showed increased tumor growth in both sham‐ and UVB‐irradiated mice. Our findings demonstrate that moderate low UVB irradiation inhibits M2‐like tumor‐associated macrophages, increases CD103+ cDC1s and promotes antitumor immunity in mice with an established tumor.
Using tumor‐bearing mouse models, we show that moderate low UVB irradiation increases the number of activated CD4+ and CD8+ T cells, CD103+ cDC1 dendritic cells, while it decreases the number of immunosuppressive, tumor‐promoting M2‐like tumor‐associated macrophages (TAMs). Deletion of Batf3 increases tumor growth in both sham‐ and UVB‐irradiated mice. Our findings demonstrate that moderate UVB irradiation promotes antitumor immunity in tumor‐bearing mice. (Created with BioRender.com).
While there is growing evidence that many epigenetically silenced genes in cancer are tumour suppressor candidates, their significance in cancer biology remains unclear. Here, we identify human ...Neuralized (NEURL), which acts as a novel tumour suppressor targeting oncogenic Wnt/β‐catenin signalling in human cancers. The expression of NEURL is epigenetically regulated and markedly suppressed in human colorectal cancer. We, therefore, considered NEURL to be a bona fide tumour suppressor in colorectal cancer and demonstrate that this tumour suppressive function depends on NEURL‐mediated oncogenic β‐catenin degradation. We find that NEURL acts as an E3 ubiquitin ligase, interacting directly with oncogenic β‐catenin, and reducing its cytoplasmic levels in a GSK3β‐ and β‐TrCP‐independent manner, indicating that NEURL‐β‐catenin interactions can lead to a disruption of the canonical Wnt/β‐catenin pathway. This study suggests that NEURL is a therapeutic target against human cancers and that it acts by regulating oncogenic Wnt/β‐catenin signalling.
Synopsis
Neuralized (NEURL) is a novel tumour suppressor targeting the oncogenic Wnt/β‐catenin pathway in colorectal cancer by promoting β‐catenin degradation independent of GSK3β and β‐TrCP.
NEURL hypermethylation is associated with poor outcomes in patients with colon cancer.
NEURL acts as a tumour suppressor in colon cancer by inhibiting cell proliferation and interrupting tumorigenesis.
NEURL targets β‐catenin as an E3 ubiquitin ligase impairing oncogenic WNT signalling in colorectal cancer.
Neuralized (NEURL) is a novel tumour suppressor targeting the oncogenic Wnt/β‐catenin pathway in colorectal cancer by promoting β‐catenin degradation independent of GSK3β and β‐TrCP.
Metastasis is a challenging clinical problem and the primary cause of death in breast cancer patients. However, there is no therapeutic agent against metastasis of breast cancer cells. Here we report ...that phloroglucinol, a natural phlorotannin component of brown algae suppresses metastatic ability of breast cancer cells. Treatment with phloroglucinol effectively inhibited mesenchymal phenotypes of basal type breast cancer cells through downregulation of SLUG without causing a cytotoxic effect. Importantly, phloroglucinol decreased SLUG through inhibition of PI3K/AKT and RAS/RAF‐1/ERK signaling. In agreement with in vitro data, phloroglucinol was also effective against in vivo metastasis of breast cancer cells, drastically suppressing their metastatic ability to lungs, and extending the survival time of mice. Collectively, our findings demonstrate a novel anticancer activity of phloroglucinol against metastasis of breast cancer cells, implicating its clinical relevance.
Phloroglucinol, a natural phlorotannin component of brown algae has an anticancer activity against metastasis of breast cancer cells to lungs. Phloroglucinol decreases EMT master regulator SLUG through inhibition of PI3K/AKT and RAS/RAF‐1/ERK signaling.
Metastasis of breast cancer is promoted by epithelial–mesenchymal transition (EMT). Emerging evidence suggests that STAT3 is a critical signaling node in EMT and is constitutively activated in many ...carcinomas, including breast cancer. However, its signaling mechanisms underlying persistent activation of STAT3 associated with EMT remain obscure. Here, we report that PIM2 promotes activation of STAT3 through induction of cytokines. Activation of STAT3 caused an increase in PIM2 expression, implicating a positive feedback loop between PIM2 and STAT3. In agreement, targeting of either PIM2, STAT3 or PIM2‐dependent cytokines suppressed EMT‐associated migratory and invasive properties through inhibition of ZEB1. Taken together, our findings identify the signaling mechanisms underlying the persistent activation of STAT3 and the oncogenic role of PIM2 in EMT in breast cancer.
PIM2 promotes epithelial‐mesenchymal transition through activation of STAT3. PIM2 activates STAT3 through induction of IL‐8 in breast cancer cells. STAT3 is constitutively activated by PIM2‐driven positive feedback loop.
Macroautophagy/autophagy is a cellular catabolic process that is implicated in several physiological and pathological processes. However, the role of epidermal autophagy in wound healing remains ...unknown. Here, using mice with genetic ablation of the essential Atg5 (autophagy related 5) or Atg7 (autophagy related 7) in their epidermis to inhibit autophagy, we show that keratinocyte autophagy regulates wound healing in mice. Wounding induces the expression of autophagy genes in mouse skin. Epidermis-specific autophagy deficiency inhibits wound closure, re-epithelialization, keratinocyte proliferation and differentiation, dermal granulation tissue formation, and infiltration of immune cells including macrophages, neutrophils, and mast cells, while it does not affect angiogenesis. Using cytokine array screening, we found that autophagy deficiency inhibits the transcription and production of the cytokine CCL2/MCP-1 by TNF. At the molecular level, TNF induces autophagic flux and the expression of autophagy genes through NFKB in epidermal keratinocytes. TNF promotes CCL2 transcription through the autophagy-AMPK-BRAF-MAPK1/3/ERK-activator protein 1 (AP1) pathway. Indeed, treating mice with recombinant CCL2 can reverse the effect of autophagy deficiency in keratinocytes. At the cellular level, we found that CCL2 induction via autophagy in keratinocytes is required not only for keratinocyte migration and proliferation but also for dermal fibroblast activation. Our findings demonstrate a critical role of epidermal autophagy in wound healing in vivo and elucidate a critical molecular machinery coordinating keratinocyte-fibroblast interaction in skin repair.
Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle; ACTB: β-actin; ADGRE1: adhesion G protein-coupled receptor E1; AMPK: AMP-activated protein kinase; AP1: activator protein 1; AP1-RE: AP1 response element; ATG: autophagy-related; ATG16L1: autophagy related 16 like 1; BECN1: beclin 1; BRAF: B-Raf proto-oncogene, serine/threonine kinase; C5: complement C5; CCL2/MCP-1: C-C motif chemokine ligand 2; CCL3: C-C motif chemokine ligand 3; CK: cytokeratin; cKO: conditional knockout; CRTC1: CREB-regulated transcription coactivator 1; CXCL1: C-X-C motif chemokine ligand 1; CXCL2: C-X-C motif chemokine ligand 2; ECM: extracellular matrix; EGF: epidermal growth factor; FGF7: fibroblast growth factor 7; GABARAPL2: GABA type A receptor associated protein like 2; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HBEGF: heparin binding EGF like growth factor; HPRT1: hypoxanthine phosphoribosyltransferase 1; IHC: immunohistochemical; IL1B: interleukin 1 beta; KRT10: keratin 10; KRT14: keratin 14; MAP1LC3B/LC3B-I/II: microtubule-associated protein 1 light chain 3 beta; MAPK1/3/ERK: mitogen-activated protein kinase 1/3; MKI67/Ki-67: marker of proliferation; MPO: myeloperoxidase; NFKB: NF-kappa B, nuclear factor kappa-light-chain-enhancer of activated B cells; NFKB-RE: NFKB response element; PDGF: platelet-derived growth factor; PECAM1: platelet and endothelial cell adhesion molecule 1; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; RELA/p65: RELA proto-oncogene, NFKB subunit; shCON: small hairpin negative control; siNC: negative control; siRNA: small interfering RNA; SP1: sp1 transcription factor; SQSTM1/p62: sequestosome 1; TGFA: transforming growth factor alpha; TGFB1: transforming growth factor beta 1; TIMP1: TIMP metallopeptidase inhibitor 1; TNF/TNF-alpha: tumor necrosis factor; TREM1: triggering receptor expressed on myeloid cells 1; WT: wild-type
Inorganic arsenic is one of the well-known human skin carcinogens. However, the molecular mechanism by which arsenic promotes carcinogenesis remains unclear. Previous studies have established that ...epigenetic changes, including changes in DNA methylation, are among the critical mechanisms that drive carcinogenesis.
-methyladenine (6mA) methylation on DNA is a widespread epigenetic modification that was initially found on bacterial and phage DNA. Only recently has 6mA been identified in mammalian genomes. However, the function of 6mA in gene expression and cancer development is not well understood. Here, we show that chronic low doses of arsenic induce malignant transformation and tumorigenesis in keratinocytes and lead to the upregulation of ALKBH4 and downregulation of 6mA on DNA. We found that reduced 6mA levels in response to low levels of arsenic were mediated by the upregulation of the 6mA DNA demethylase ALKBH4. Moreover, we found that arsenic increased ALKBH4 protein levels and that ALKBH4 deletion impaired arsenic-induced tumorigenicity
and in mice. Mechanistically, we found that arsenic promoted ALKBH4 protein stability through reduced autophagy. Together, our findings reveal that the DNA 6mA demethylaseALKBH4 promotes arsenic tumorigenicity and establishes ALKBH4 as a promising target for arsenic-induced tumorigenesis.
Ionizing radiation is widely used for patient with glioblastoma (GBM). However, the effect of radiation on patient survival is marginal and upon recurrence tumors frequently shift toward mesenchymal ...subtype adopting invasiveness. Here, we show that ionizing radiation affects biomechanical tension in GBM microenvironment and provides proinvasive extracellular signaling cue, hyaluronic acid (HA)-rich condition. In response to radiation, HA production was increased in GBM cells by HA synthase-2 (HAS2) that was transcriptionally upregulated by NF-ĸB. Notably, NF-ĸB was persistently activated by IL-1α-feedback loop, making HA abundance in tumor microenvironment after radiation. Radiation-induced HA abundance causally has been linked to invasiveness of GBM cells by generating movement track as an extracellular matrix, and by acting as a signaling ligand for CD44 receptor, leading to SRC activation, which is sufficient for mesenchymal shift of GBM cells. Collectively, our findings provide an explanation for the frequent brain tumor relapse after radiotherapy, and potential therapeutic targets to block mesenchymal shift upon relapse.
Understanding the molecular mechanisms that underlie the aggressive behavior and relapse of breast cancer may help in the development of novel therapeutic interventions. CUB-domain-containing protein ...1 (CDCP1), a transmembrane adaptor protein, is highly maintained and required in the context of cellular metastatic potential in triple-negative breast cancer (TNBC). For this reason, gene expression levels of CDCP1 have been considered as a prognostic marker in TNBC. However, not rarely, transcript levels of genes do not reflect always the levels of proteins, due to the post-transcriptional regulation. Here we show that miR-17/20a control the FBXL14 E3 ligase, establishing FBXL14 as an upstream regulator of the CDCP1 pathway. FBXL14 acts as an novel interaction partner of CDCP1, and facilitates its ubiquitination and proteasomal degradation with an enhanced capacity to suppress CDCP1 protein stability that eventually prevents CDCP1 target genes involved in breast cancer metastasis. Our findings first time uncovers the regulatory mechanism of CDCP-1 protein stabilization, more predictable criteria than gene expression levels for prognosis of breast cancer patients.
Somatosensory evoked potentials (SEPs) have been widely used to assess neurological function in clinical practice. A good understanding of the association between SEP signals and neurological ...function is helpful for precise diagnosis of impairment location. Previous studies on SEPs have been reported in animal models. However, few studies have reported the relationships between SEP waveforms in animals and those in humans. In this study, we collected normal SEP waveforms and decomposed them into specific time-frequency components (TFCs). Our results showed three stable TFC distribution regions in intact goats and rats and in humans. After we induced spinal cord injury in the animal models, a greater number of small TFC distribution regions were observed in the injured goat and rat groups than in the normal group. Moreover, there were significant correlations (P < 0.05) and linear relationships between the main SEP TFCs of the human group and those of the goat and rat groups. A stable TFC distribution of SEP components was observed in the human, goat and rat groups, and the TFC distribution modes were similar between the three groups. Results in various animal models in this study could be translated to future clinical studies based on SEP TFC analysis. Human studies were approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (approval No. UM 05-312 T/975) on December 5, 2005. Rat experiments were approved by the Committee on the Use of Live Animals in Teaching and Research of Li Ka Shing Faculty of Medicine of the University of Hong Kong (approval No. CULART 2912-12) on January 28, 2013. Goat experiments were approved by the Animal Ethics Committee of Affiliated Hospital of Guangdong Medical University (approval No. GDY2002132) on March 5, 2018.
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