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Long non‐coding RNAs (lncRNAs) play an important role in the progression of gastric cancer (GC), but its specific regulatory mechanism remains to be further studied. We previously identified that lncRNA B3GALT5‐AS1 was upregulated in GC serum. Here, we investigated the functions and molecular mechanisms of B3GALT5‐AS1 in GC tumorigenesis. qRT‐PCR was used to detect B3GALT5‐AS1 expression in GC. EdU, CCK‐8, and colony assays were utilized to assess the proliferation ability of B3GAL5‐AS1, and transwell, tube formation assay were used to assess the invasion and metastasis ability. Mechanically, FISH and nuclear plasmolysis PCR identified the subcellular localization of B3GALT5‐AS1. RIP and CHIP assays were used to analyse the regulation of B3GALT5‐AS1 and B3GALT5. We observed that B3GALT5‐AS1 was highly expressed in GC, and silencing B3GALT5‐AS1 could inhibit the proliferation, invasion, and migratory capacities of GC. Additionally, B3GALT5‐AS1 was bound to WDR5 and modulated the expression of B3GALT5 via regulating the ZEB1/β‐catenin pathway. High‐expressed B3AGLT5‐AS1 promoted GC tumorigenesis and regulated B3GALT5 expression via recruiting WDR5. Our study is expected to provide a new idea for clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNAs (lncRNAs) have been reported to play a key role in gastric cancer (GC) tumorigenesis. However, the clinical application value of serum lncRNAs in GC has remained largely unknown. We investigated the role of a novel lncRNA named CTC-497E21.4 in the diagnosis and the prognosis of GC. Methods: We focused on evaluation of lncRNA CTC-497E21.4 by real-time fluorescent quantitative polymerase chain reaction (RTFQ-PCR). The study involved following aspects: (1) confirmation of the higher lncRNA CTC-497E21.4 expression in different types of GC specimens than corresponding controls; (2) evaluation of monitoring tumor dynamics by the serum lncRNA CTC-497E21.4 assay; (3) evaluation of the prognostic value of lncRNA CTC-497E21.4 assay in GC. Results: (1) The method of RTFQ-PCR detection of lncRNA CTC-497E21.4 was evaluated to have high sensitivity and specificity. (2) The expression levels of lncRNA CTC-497E21.4 were higher in GC patients compared with corresponding controls (p<0.001), and the combination of serum lncRNA CTC-497E21.4, CEA and CA19-9 could improve diagnostic sensitivity (96.36%). (3) The serum lncRNA CTC-497E21.4 expression levels were lower in postoperative samples than preoperative samples (p=0.0021) and survival curves downloaded from TCGA showed high lncRNA CTC-497E21.4 levels were associated with poor OS of GC (p=0.0351). Conclusions: lncRNA CTC-497E21.4 may be a potential biomarker for the diagnosis and the prognosis of GC. [ABSTRACT FROM AUTHOR]

Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases. Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis. [ABSTRACT FROM AUTHOR]

Deficiency of autophagy protein beclin 1 is implicated in tumorigenesis and neurodegenerative diseases, but the molecular mechanism remains elusive. Previous studies showed that Beclin 1 coordinates the assembly of multiple VPS34 complexes whose distinct phosphatidylinositol 3-kinase III (PI3K-III) lipid kinase activities regulate autophagy at different steps. Recent evidence suggests a function of beclin 1 in regulating multiple VPS34-mediated trafficking pathways beyond autophagy; however, the precise role of beclin 1 in autophagy-independent cellular functions remains poorly understood. Herein we report that beclin 1 regulates endocytosis, in addition to autophagy, and is required for neuron viability in vivo. We find that neuronal beclin 1 associates with endosomes and regulates EEA1/early endosome localization and late endosome formation. Beclin 1 maintains proper cellular phosphatidylinositol 3-phosphate (PI(3)P) distribution and total levels, and loss of beclin 1 causes a disruption of active Rab5 GTPase-associated endosome formation and impairment of endosome maturation, likely due to a failure of Rab5 to recruit VPS34. Furthermore, we find that Beclin 1 deficiency causes complete loss of the UVRAG-VPS34 complex and associated lipid kinase activity. Interestingly, beclin 1 deficiency impairs p40phox-linked endosome formation, which is rescued by overexpressed UVRAG or beclin 1, but not by a coiled-coil domain-truncated beclin 1 (a UVRAG-binding mutant), Atg14L or RUBICON. Thus, our study reveals the essential role for beclin 1 in neuron survival involving multiple membrane trafficking pathways including endocytosis and autophagy, and suggests that the UVRAG-beclin 1 interaction underlies beclin 1's function in endocytosis. [ABSTRACT FROM AUTHOR]

Either activation of mTORC1 due to loss of Tsc1 (tuberous sclerosis complex 1) or defective hepatic autophagy due to loss of Atg5 leads to spontaneous liver tumorigenesis in mice. The purpose of this study was to investigate the mechanisms by which autophagy contributes to the hepatic metabolic changes and tumorigenesis mediated by mTORC1 activation. Atg5 Flox/Flox (Atg5 F/F) and Tsc1 F/F mice were crossed with albumin-Cre mice to generate liver-specific Atg5 knockout (L- Atg5 KO), L- Tsc1 KO and L- Atg5/Tsc1 double KO (DKO) mice. These mice were crossed with p62 / Sqstm1 F/F (p62) and whole body Nrf2 KO mice to generate L-A tg5/Tsc1/p62 and L- Atg5/Tsc1-Nrf2 triple KO mice. These mice were housed for various periods up to 12 months, and blood and liver tissues were harvested for biochemical and histological analysis Deletion of Atg5 in L- Tsc1 KO mice inhibited liver tumorigenesis but increased mortality and was accompanied by drastically enhanced hepatic ductular reaction (DR), hepatocyte degeneration and metabolic reprogramming. Deletion of p62 reversed DR, hepatocyte degeneration and metabolic reprogramming as well as the mortality of L- Atg5/Tsc1 DKO mice, but unexpectedly promoted liver tumorigenesis via activation of a group of oncogenic signaling pathways. Nrf2 ablation markedly improved DR with increased hepatocyte population and improved metabolic reprogramming and survival of the L- Atg5/Tsc1 DKO mice without tumor formation. Decreased p62 and increased mTOR activity were also observed in a subset of human hepatocellular carcinomas. These results reveal previously undescribed functions of hepatic p62 in suppressing tumorigenesis and regulating liver cell repopulation and metabolic reprogramming resulting from persistent mTORC1 activation and defective autophagy. Metabolic liver disease and viral hepatitis are common chronic liver diseases and risk factors of hepatocellular carcinoma, which are often associated with impaired hepatic autophagy and increased mTOR activation. Using multiple genetically engineered mouse models of defective hepatic autophagy and persistent mTOR activation, we dissected the complex mechanisms behind this observation. Our results uncovered an unexpected novel tumor suppressor function of p62/ Sqstm1 , which regulated liver cell repopulation, ductular reaction and metabolic reprogramming in liver tumorigenesis. [Display omitted] • Mouse livers with persistent mTOR activation and defective autophagy developed ductular reaction with metabolic reprogramming. • mTOR activation-induced liver tumorigenesis was inhibited in mice lacking hepatic autophagy and vice versa. • Loss of p62/Sqstm1 rescued ductular reaction, liver cell remodeling and metabolic reprograming in these mice. • p62/Sqstm1, a previously known oncogenic protein, paradoxically acted as a tumor suppressor and inhibited liver tumorigenesis in these mice. • Decreased p62 and increased mTOR activity was found in a subset of human patients with hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Autophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression. [ABSTRACT FROM AUTHOR]

The article discusses an expression of concern for the article "HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers".