Gastroenterologies
Abstract
Nonalcoholic steatohepatitis (NASH) is closely related to liver fibrosis. The role of coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) in NASH remains unknown. CHCHD2’s functions as a transcription factor have received much less attention than those in mitochondria. Herein, we systematically characterized the role of CHCHD2 as a transcription factor by chromatin immunoprecipitation sequencing and found its target genes were enriched in nonalcoholic fatty liver disease (NAFLD). Overall, CHCHD2 expression was found to be increased in the livers of patients with NAFLD and those of NASH mice. In line with these findings, CHCHD2 deficiency ameliorated NASH- and thioacetamide-induced liver fibrosis, whereas hepatocyte-specific CHCHD2 overexpression promoted liver fibrosis in NASH mice via Notch signaling. Specifically, CHCHD2-overexpressing hepatocytes activated hepatic stellate cells by upregulating osteopontin levels, a downstream mediator of Notch signals. Moreover, Notch inhibition attenuated CHCHD2 overexpression–induced liver fibrosis in vivo and in vitro. Then we found lipopolysaccharide-induced CHCHD2 expression in hepatocytes was reverted by verteporfin, an inhibitor that disrupts the interaction between Yes-associated protein (YAP) and transcriptional enhanced associate domains (TEADs). In addition, CHCHD2 levels were positively correlated with those of TEAD1 in human samples. In conclusion, CHCHD2 is upregulated via YAP/TAZ-TEAD in NASH livers and consequently promotes liver fibrosis by activating the Notch pathway and enhancing osteopontin production.
Authors
Yue Li, Wenjing Xiu, Jingwen Xu, Xiangmei Chen, Guangyan Wang, Jinjie Duan, Lei Sun, Ben Liu, Wen Xie, Guangyin Pu, Qi Wang, Chunjiong Wang
Abstract
Acute and chronic intestinal inflammation is associated with epithelial damage, resulting in mucosal wounds in the forms of erosions and ulcers in the intestinal tract. Intestinal epithelial cells (IECs) and immune cells in the wound milieu secrete cytokines and lipid mediators to influence repair. Leukotriene B4 (LTB4), a lipid chemokine, binds to its receptor BLT1 and promotes migration of immune cells to sites of active inflammation, however a role for intestinal epithelial BLT1 during mucosal wound repair is not known. Here we report that BLT1 is expressed in IECs both in vitro and in vivo, where it functions as a receptor not only for LTB4 but also for another ligand Resolvin E1. Intestinal epithelial BLT1 expression is increased when epithelial cells are exposed to an inflammatory microenvironment. Using human and murine primary colonic epithelial cells, we reveal that LTB4-BLT1 axis promotes epithelial migration and proliferation leading to accelerated epithelial wound repair. Furthermore, in vivo intestinal wound repair experiments in BLT1-deficient mice and bone marrow chimeras demonstrate an important contribution of epithelial BLT1 during colonic mucosal wound repair. Taken together, our findings show a novel pro-repair in IEC mechanism mediated by BLT1 signaling.
Authors
Shusaku Hayashi, Chithra K. Muraleedharan, Makito Oku, Sunil Tomar, Simon P. Hogan, Miguel Quiros, Charles A. Parkos, Asma Nusrat
Abstract
Intestinal epithelial integrity is commonly disrupted in patients with critical disorders, but the exact underlying mechanisms are unclear. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control different cell functions and are involved in pathologies. Here, we investigated the role of T-UCRs in intestinal epithelial homeostasis and identified T-UCR uc.230 as a major regulator of epithelial renewal, apoptosis, and barrier function. Compared with controls, intestinal mucosal tissues from patients with ulcerative colitis and from mice with colitis or fasted for 48 hours had increased levels of uc.230. Silencing uc.230 inhibited the growth of intestinal epithelial cells (IECs) and organoids and caused epithelial barrier dysfunction. Silencing uc.230 also increased IEC vulnerability to apoptosis, whereas increasing uc.230 levels protected IECs against cell death. In mice with colitis, reduced uc.230 levels enhanced mucosal inflammatory injury and delayed recovery. Mechanistic studies revealed that uc.230 increased CUG-binding protein 1 (CUGBP1) by acting as a natural decoy RNA for miR-503, which interacts with Cugbp1 mRNA and represses its translation. These findings indicate that uc.230 sustains intestinal mucosal homeostasis by promoting epithelial renewal and barrier function and that it protects IECs against apoptosis by serving as a natural sponge for miR-503, thereby preserving CUGBP1 expression.
Authors
Ting-Xi Yu, Sudhakar Kalakonda, Xiangzheng Liu, Naomi Han, Hee K. Chung, Lan Xiao, Jaladanki N. Rao, Tong-Chuan He, Jean-Pierre Raufman, Jian-Ying Wang
Abstract
Acute pancreatitis (AP) is a local and/or systemic inflammatory disease that starts with acinar cell injury and necrosis, which has no effective medical treatment and thus remains a life-threatening condition. Interleukin-37 (IL-37), a natural immunomodulator, has demonstrated an anti-inflammatory effect; however, the role of IL-37 in AP remains unknown. The serum IL-37 levels of 39 healthy controls and 94 AP patients were measured. Cholecystokinin was applied to induce pancreatic acinar cell injury in vitro. Classical experimental AP models, such as caerulein, L-arginine, and Taurocholic acid sodium salt were included in the in vivo study. A transgenic mouse model with the IL-37 gene and administration of recombinant IL-37 were used to further investigate the function of IL-37 in AP. Pancreas-specific GSDMD knockout mice were used to explore the protective mechanism of IL-37. Our results showed that serum IL-37 levels of human were negatively correlated with the severity of AP. Furthermore, transgenic IL-37 mice and supplementation with recombinant IL-37 could both protect against AP. Mechanistically, IL-37 was able to suppress pyroptosis of injured acinar cells, and specific depletion of GSDMD in the pancreas counteracted the protective effect of IL-37. Our study demonstrates that IL-37 protects against acinar cell pyroptosis in AP.
Authors
Nan Ma, Chenchen Yuan, Juanjuan Shi, Qingtian Zhu, Yang Liu, Xiaojie Ma, Baiqiang Li, Weijuan Gong, Jing Xue, Guotao Lu, Weiqin Li, Jieshou Li
Abstract
Although Barrett’s metaplasia of the esophagus (BE) is the only known precursor lesion to esophageal adenocarcinomas (EACs), drivers of cellular transformation in BE remain incompletely understood. We use an artificial intelligence–guided network approach to study EAC initiation and progression. Key predictions are subsequently validated in a human organoid model, in patient-derived biopsy specimens of BE, a case-control study of genomics of BE progression, and in a cross-sectional study of 113 patients with BE and EACs. Our model classified healthy esophagus from BE and BE from EACs in several publicly available gene expression data sets (n = 932 samples). The model confirmed that all EACs must originate from BE and pinpointed a CXCL8/IL8↔neutrophil immune microenvironment as a driver of cellular transformation in EACs and gastroesophageal junction adenocarcinomas. This driver is prominent in White individuals but is notably absent in African Americans (AAs). Network-derived gene signatures, independent signatures of neutrophil processes, CXCL8/IL8 expression, and an absolute neutrophil count (ANC) are associated with risk of progression. SNPs associated with changes in ANC by ethnicity (e.g., benign ethnic neutropenia [BEN]) modify that risk. Findings define a racially influenced immunological basis for cell transformation and suggest that BEN in AAs may be a deterrent to BE→EAC progression.
Authors
Pradipta Ghosh, Vinicius J. Campos, Daniella T. Vo, Caitlin Guccione, Vanae Goheen-Holland, Courtney Tindle, Guilherme S. Mazzini, Yudou He, Ludmil B. Alexandrov, Scott M. Lippman, Richard R. Gurski, Soumita Das, Rena Yadlapati, Kit Curtius, Debashis Sahoo
Abstract
High-fat diet (HFD) contributes to the increased incidence of colorectal cancer; but the mechanisms are unclear. We found that R-spondin 3 (Rspo3), a ligand for LGR4 and LGR5, was the major subtype and produced by myofibroblasts beneath the crypts in the intestine; HFD upregulated colonic Rspo3, LGR4, LGR5 and β-catenin gene expressions in specific pathogen free rodents, but not in germfree mice, and the upregulations were prevented by bile acids (BA) binder, cholestyramine (CHO) or antibiotic treatment, indicating mediating by both BA and gut microbiota. CHO or antibiotic treatments prevented HFD-induced enrichment of Lachnospiraceae and Rumincoccaceae, which are capable of transforming 10 into 20 BA. Oral administration of deoxycholic acid (DCA), or inoculation of a combination of BA deconjugator Lactobacillus plantarum and 7-α-dehydroxylase-containing Clostridium scindens with HFD to germfree mice increased colonic Rspo3 mRNA, indicating that formation of 20 BA by gut microbiota is responsible for HFD-induced upregulation of Rspo3. In primary myofibroblasts DCA increased Rpso3 mRNA via TGR5. Finally, we showed that CHO or conditional deletion of Rspo3 prevented HFD- or DCA- induced intestinal proliferation. We conclude that secondary BA is responsible for HFD-induced upregulation of Rspo3, which in turn mediates HFD-induced intestinal epithelial proliferation.
Authors
Ji-Yao Li, Merritt Gillilland III, Allen A. Lee, Xiaoyin Wu, Shi-Yi Zhou, Chung Owyang
Abstract
Metastatic pancreatic cancer (PDAC) has a poor clinical outcome with a 5-year survival rate below 3%. Recent transcriptome profiling of PDAC biopsies has identified 2 clinically distinct subtypes — the “basal-like” (BL) subtype with poor prognosis and therapy resistance compared with the less aggressive and drug-susceptible “classical” (CLA) subtype. However, the mechanistic events and environmental factors that promote the BL subtype identity are not very clear. Using preclinical models, patient-derived xenografts, and FACS-sorted PDAC patient biopsies, we report here that the axon guidance receptor, roundabout guidance receptor 3 (ROBO3), promotes the BL metastatic program via a potentially unique AXL/IL-6/phosphorylated STAT3 (p-STAT3) regulatory axis. RNA-Seq identified a ROBO3-mediated BL-specific gene program, while tyrosine kinase profiling revealed AXL as the key mediator of the p-STAT3 activation. CRISPR/dCas9-based ROBO3 silencing disrupted the AXL/p-STAT3 signaling axis, thereby halting metastasis and enhancing therapy sensitivity. Transcriptome analysis of resected patient tumors revealed that AXLhi neoplastic cells associated with the inflammatory stromal program. Combining AXL inhibitor and chemotherapy substantially restored a CLA phenotypic state and reduced disease aggressiveness. Thus, we conclude that a ROBO3-driven hierarchical network determines the inflammatory and prometastatic programs in a specific PDAC subtype.
Authors
Niklas Krebs, Lukas Klein, Florian Wegwitz, Elisa Espinet, Hans Carlo Maurer, Mengyu Tu, Frederike Penz, Stefan Küffer, Xingbo Xu, Hanibal Bohnenberger, Silke Cameron, Marius Brunner, Albrecht Neesse, Uday Kishore, Elisabeth Hessmann, Andreas Trumpp, Philipp Ströbel, Rolf A. Brekken, Volker Ellenrieder, Shiv K. Singh
Abstract
Identification of molecular subtypes that reflect different prognoses and treatment responses, especially immune checkpoint inhibitors (ICIs) in esophageal squamous cell carcinoma (ESCC), is essential for treatment decisions. We performed targeted sequencing in 201 patients with ESCC to discover genetic subtypes and validate our findings via multiple data sets. We identified 3 driver genes (FCGBP, GRIN2B, and FRY), and recurrent truncating mutations in FRY impaired its tumor-suppressive function and promoted tumor proliferation. A 3-gene mutation signature (FAT1, FAT3, and FRY) recognized a molecular subtype named “FAT/FRY” with frequent Hippo pathway–related mutations. In multiple ESCC cohorts, the patients with the FAT/FRY subtype had poorer prognosis than did patients in the WT group. Transcriptome analysis indicated that the FAT/FRY subtype was characterized by inactivation of the Hippo pathway, hypoxia, chemoresistance, higher infiltration of CD8+ T cells and activated DCs, and a transcriptome similar to that of cancer responders. Furthermore, the 3-gene signature predicted better survival for patients treated with ICIs, partially explained by its positive correlation with the tumor mutation burden and neoantigen burden. The 3-gene signature is a biomarker to recognize the FAT/FRY molecular subtype, evaluate prognosis, and select potential beneficiaries of ICIs in ESCC.
Authors
Zihang Mai, Jianye Yuan, Hong Yang, Shuogui Fang, Xiuying Xie, Xinye Wang, Jiaxin Xie, Jing Wen, Jianhua Fu
Abstract
Junctional adhesion molecule-A (JAM-A) is expressed in several cell types including epithelial and endothelial cells as well as some leukocytes. In intestinal epithelial cells (IEC), JAM-A localizes to cell junctions and plays a role in regulating barrier function. In vitro studies with model cell lines have shown that JAM-A contributes to IEC migration, however in vivo studies investigating the role of JAM-A in cell migration-dependent processes such as mucosal wound repair have not been performed. In this study, we developed an inducible intestinal epithelial-specific JAM-A knockdown mouse model (Jam-aER-ΔIEC). While acute induction of IEC-specific loss of JAM-A did not result in spontaneous colitis, such mice had significantly impaired mucosal healing after chemically induced colitis and after biopsy colonic wounding. In vitro primary cultures of JAM-A deficient IEC demonstrated impaired migration in wound healing assays. Mechanistic studies revealed that JAM-A stabilizes formation of protein signaling complexes containing Rap1A/Talin/β1-integrin at focal adhesions of migrating IECs. Loss of JAM-A in primary IEC led to decreased Rap1A activity and protein levels of Talin and β1-integrin and a reduction in focal adhesion structures. These findings suggest that epithelial JAM-A plays a critical role in controlling mucosal repair in vivo through dynamic regulation of focal adhesions
Authors
Shuling Fan, Kevin Boerner, Chithra K. Muraleedharan, Asma Nusrat, Miguel Quiros, Charles A. Parkos
Abstract
Long non-coding RNA (lncRNA) plays a crucial role in the pathogenesis of various diseases, including colorectal cancer (CRC). The gene mutations of Adenomatous polyposis coli (APC) were found in most colorectal cancer patients. They are functioned as an important inducer of tumorigenesis. Based on our microarray results, we identified a specific upregulated lncRNA in colorectal cancer (SURC). Further analysis showed that high SURC expression correlated with poorer disease-free survival and overall survival in patients with colorectal cancer. Besides, we found that mutated APC genes can promote the transcription of SURC by reducing the degradation of β-catenin protein in colorectal cancer. Functional assays revealed that knockdown of SURC impaired CRC cell proliferation, colony formation, cell cycle and tumor growth. Additionally, SURC can promote CCND2 expression by inhibiting the expression of miR-185-5p in CRC cells. In conclusion, we demonstrate that SURC is a specific upregulated lncRNA in CRC and the SURC/miR-185-5p/CCND2 axis may be targetable for CRC diagnosis and therapy.
Authors
Junshu Li, Yanhong Ji, Na Chen, Huiling Wang, Chao Fang, Xiaonan Yin, Zhiyuan Jiang, Zhexu Dong, Dan Zhu, Jiamei Fu, Wencheng Zhou, Ruiyi Jiang, Ling He, Zhang Hantao, Gang Shi, Lin Cheng, Xiaolan Su, Lei Dai, Hongxin Deng
No posts were found with this tag.
