Advanced oxidation protein products induce Paneth cells defects by endoplasmic reticulum stress in Crohn's disease.

Paneth cells (PC) play a key role in the innate immune response of intestine epithelium, and PC defects contribute to the pathogenesis of Crohn's disease (CD). In this study, we utilized active CD tissues and advanced oxidation protein products (AOPP)-challenged C57BL/6 mouse model to investigate the effect of AOPP on PC defects in CD. We found that AOPP accumulated in active CD tissues and was negatively associated with lysozyme expression, while positively correlated with the presence of ER stress markers. Furthermore, AOPP treatment induced PC defects mainly through excessive ER stress in vivo, and AOPP also caused mitochondria-associated ER membranes formation and mitochondrial dysfunction. In addition, the effects of AOPP could be attenuated by the administration of ER stress inhibitor, TUDCA. These findings suggest a pathogenic role of AOPP contributing to PC defects and may provide the basis for developing new strategies to managing CD.

TRMT6 promotes hepatocellular carcinoma progression through the PI3K/AKT signaling pathway.

BACKGROUND: Hepatocellular carcinoma is one of the most common and deadly cancers. The aim of this study was to elucidate the role of tRNA methyltransferase 6 (TRMT6) during HCC progression. METHODS: The role of TRMT6 in the progression and prognosis of HCC was confirmed by analysis of online databases and clinical human samples. The effects of up-regulation or down-regulation of TRMT6 on HCC cell proliferation and PI3K/AKT pathway-related protein expressions were verified. The molecular mechanism was investigated in vivo by constructing subcutaneous xenograft tumor model. RESULTS: TRMT6 was overexpressed in HCC tissues and associated with Tumour-Node-Metastasis (TNM) stage, primary tumor (T) and regional lymph node (N) classification. TRMT6 expressions in HCC cell lines were higher than that in normal liver cell. TRMT6 overexpression can promote HCC cell proliferation, increase the number of S phase cells. Interference with TRMT6 reduced the PI3K/AKT pathway-related protein expressions, and was reversed by the addition of IGF1. Interference with TRMT6 inhibited tumor growth in vivo and was related to PI3K/AKT pathway. CONCLUSIONS: Overexpression of TRMT6 promote HCC cell proliferation in vivo and in vitro through PI3K/AKT/mTOR axis, which provides a potential choice for the treatment of HCC in clinical practice.

Overexpression of CENPL mRNA potentially regulated by miR-340-3p predicts the prognosis of pancreatic cancer patients.

BACKGROUND: In our previous study it was found that CENPL was overexpressed in hepatocellular carcinoma and significantly predicted patient's prognosis. However, the expression and prognostic value of CENPL in other gastrointestinal tumors remain unknown. Therefore, we investigated the expression and prognostic value of CENPL in esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), pancreatic adenocarcinoma (PAAD), colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ). METHODS: In this study, Oncomine, GEPIA, OncoLnc, TIMER, cBioPortal, miRWalk and ENCORI databases were used to analyze the level of CENPL mRNA, prognostic value and potential regulatory mechanism of CENPL mRNA in tumors. The CENPL expression and clinicopathological data regarding PAAD were from the UCSC Xena database and univariate and multivariate Cox regression analyses were performed using R (Version 3.6.3). Immunohistochemical staining was used to verify the expression of CENPL protein in clinical specimens. Cytoscape (Version: 3.7.2) was used to visualize microRNA (miRNA) that potentially regulates CENPL. RESULTS: Gene differential expression analysis showed that CENPL mRNA was significantly overexpressed in ESCA, STAD, PAAD, COAD and READ (p < 0.01). The overexpression of CENPL mRNA was significantly correlated with the poor prognosis of PAAD patients (p < 0.05). However, there was no significant correlation between the level of CENPL mRNA and the prognosis of ESCA, STAD, COAD and READ patients (p > 0.05). Univariate and multivariate Cox regression analyses suggested that CENPL was a prognostic risk factor for PAAD. The mutation rate of CENPL in PAAD was 2.2% (17/850). There was no significant correlation between the CENPL expression and the infiltration levels of immune cells in PAAD (|Cor|< 0.5). Immunohistochemical staining showed that CENPL was overexpressed in 42% (11/26) of PAAD specimens, which was significantly higher compared with that in the normal tissues. The expression of miR-340-3p and miR-484 in PAAD were significantly lower than in the normal tissues (p < 0.05) and PAAD patients with lower expression of miR-340-3p had poorer prognosis (p < 0.05). CONCLUSION: CENPL potentially regulated by miR-340-3p, is overexpressed in PAAD and predicts patient's prognosis, suggestive of a diagnostic and prognostic value in PAAD patients.

Advanced oxidation protein products impair autophagic flux in macrophage by inducing lysosomal dysfunction via activation of PI3K-Akt-mTOR pathway in Crohn's disease.

Dysfunction in macrophages is involved in the pathogenesis of various diseases, including Crohn's disease (CD). Previously, we found that advanced oxidation protein products (AOPPs) were predominantly deposited in macrophages in the intestinal lamina propria of CD patients. However, whether AOPPs contributes to macrophage dysfunction in CD and the underlying mechanism remains unknown. This study aimed to investigate the effects of AOPPs on macrophages functions in CD. In the present study, we discovered increased AOPPs levels were positively correlated with impaired autophagy in macrophages of CD patients. AOPPs could impair autophagic flux by inducing lysosomal dysfunction in RAW264.7 cell line and macrophages in AOPPs-treated mice, evidenced by increased number of autophagosomes, blocked degradation of autophagy-related proteins (LC3B-II and SQSTM1/p62), and decreased activity of lysosomal proteolytic enzymes after AOPPs challenge. Besides, AOPPs could also promote M1 polarization in RAW264.7 cells and bone marrow derived macrophages (BMDMs) in AOPPs-treated mice. In addition, our study revealed that PI3K-AKT-mTOR-TFEB pathway was activated by AOPPs in macrophages. Inhibition of the PI3K pathway effectively alleviated AOPPs-induced autophagy impairment and M1 polarization both in vitro and in vivo, thus reducing intestinal inflammation in AOPPs-challenged mice. Together, this study demonstrates that AOPPs-induced autophagy impairment in macrophages is crucial for CD progression.

S100A16 suppresses the proliferation, migration and invasion of colorectal cancer cells in part via the JNK/p38 MAPK pathway.

S100 calcium binding protein A16 (S100A16) is the most recent member of the S100 calcium-binding protein family. The function of S100A16 has been associated with various types of cancer; however, its role in colorectal cancer (CRC) remains unknown. Therefore, the aim of the present study was to investigate the role of S100A16 in CRC progression. The Oncomine dataset used in the current study revealed that the expression of S100A16 was decreased in CRC compared with normal colorectal tissues. Similar results were also determined via immunohistochemistry. In addition, a negative association was identified between S100A16 expression and the prognosis of patients with CRC. Further functional experiments revealed that S100A16 knockdown promoted the proliferation, migration and invasion of HCT116 and SW480 cells, and vice versa in Lovo cells. Epithelial-mesenchymal transition (EMT) was promoted and the JNK/p38 MAPK pathway was activated in HCT116 cells following S100A16 knockdown, as determined via western blotting. Furthermore, S100A16 silencing promoted the migration and invasion of cells. EMT was also reversed when cells were treated with the JNK inhibitor (SP600125) or the p38 inhibitor (SB203580). In summary, the results of the present study demonstrated that S100A16 suppressed the proliferation, migration and invasion of CRC cells partially via the JNK/p38 MAPK signalling pathway and subsequent EMT mediation.