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1.
Sci Rep ; 11(1): 565, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436852

RESUMO

Increasing evidence suggests that circular RNAs (circRNAs) play critical roles in various pathophysiological activities. However, the role of circRNAs in inflammatory bowel disease (IBD) remains unclear. Here we report the potential roles of hsa_circRNA_103765 in regulating cell apoptosis induced by TNF-α in Crohn's disease (CD). We identify that CircRNA_103765 expression was significantly upregulated in peripheral blood mononuclear cells (PBMCs) of patients with active IBD. A positive correlation with TNF-α significantly enhanced circRNA_103765 expression in CD, which was significantly reversed by anti-TNF-α mAb (infliximab) treatment. In vitro experiments showed that TNF-α could induce the expression of circRNA_103765, which was cell apoptosis dependent, while silencing of circRNA_103765 could protect human intestinal epithelial cells (IECs) from TNF-α-induced apoptosis. In addition, circRNA_103765 acted as a molecular sponge to adsorb the miR-30 family and impair the negative regulation of Delta-like ligand 4 (DLL4). Collectively, CircRNA_103765 is a novel important regulator of the pathogenesis of IBD via sponging miR-30 family-mediated DLL4 expression changes. Blockade of circRNA_103765 could serve as a novel approach for the treatment of IBD patients.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33492448

RESUMO

Although a number of studies have revealed the important roles of miR-34a in cancer, the regulatory roles of miR-34a in cancer immune response remain largely unknown. Our present study demonstrated a mechanism underlying miR-34a-mediated cancer immune evasion via a SIRT1/NF-κB/B7-H3/TNF-α axis. miR-34a upregulated B7-H3, an important immune checkpoint molecule, through direct inhibition of SIRT1 and consequent acetylation of NF-κB subunit p65 (a-p65), which promoted B7-H3 transcription by direct binding to its promoter. The elevated B7-H3 induced production of pro-inflammatory cytokines including TNF-α. This was further confirmed in the colon of Mir34a-deficient mice, where Sirt1 expression was boosted, and the expressions of a-p65, B7h3, and Tnf were repressed. Consequently, the in vivo inhibitory activity of miR-34a on colorectal cancer (CRC) was eradicated by the reinforced B7-H3 and TNF-α. In conclusion, our study uncovered an etiological mechanism underlying miR-34a-mediated CRC immune evasion through inhibition of SIRT1 and promotion of NF-κB/B7-H3/TNF-α axis.

3.
Cancer Invest ; : 1-13, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33356637

RESUMO

Background: To investigate how EHD2 influences the development of colon cancer. Methods: Immunohistochemistry of 90 colon cancer tissue specimens were determined the expression of EHD2. The lentivirus-EHD2-transfected colon cancer cells were conducted to evaluate the biological behaviors. Results: EHD2 was closely associated with clinic pathological parameters (p < 0.001). EHD2 upregulation was relative with a longer overall survival. The results of the univariate and multivariate analyses indicated that EHD2 could be an independent prognosis marker. EHD2 overexpression suppressed cell invasion and proliferation, but enhanced cell apoptosis and cell cycle arrest. Conclusions: EHD2 might represent a therapeutic target of colon cancer. IMPACT STATEMENT What is already known on this subject? Membrane trafficking is crucial for cell proliferation, differentiation and apoptosis, especially tumorigenesis and development. EHD2 proteins play an important role in the regulation of membrane trafficking in endocytosis. EHD2 has been suggested to participate in the occurrence of some malignancies. What are the new findings? EHD2 could be an independent prognosis marker in colon cancer. EHD2 overexpression suppressed cell invasion and proliferation, but enhanced cell apoptosis and cell cycle arrest in vitro. EHD2 overexpression markedly increased the expression of EMT marker E-cadherin in colon cancer. How might it impact on clinical practice in the foreseeable future? EHD2 overexpression may inhibit tumorigenesis in colon cancer through the modulation of E-cadherin, the critical marker of EMT which is closely related to invasion and distant metastasis of tumor cells.

4.
Immunogenetics ; 72(9-10): 467-474, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33284381

RESUMO

Susceptibility to primary biliary cholangitis (PBC) is in part genetically determined. In our previous PBC genome-wide association study (GWAS) in 1118 Han Chinese PBC and 4036 controls, we noted that multiple SNPs in the runt-related transcription factor 3 (RUNX3) regions showed a nominally significant association. The tag SNP rs7529070 was genotyped using a TaqMan assay in a separately collected 1435 PBC and 3205 controls. A meta-analysis with a combined 2553 PBC and 7241 controls showed that rs7529070 is still nominally associated with PBC (p = 1.7 × 10-4, odds ratio (OR) = 1.18, 95% confidence interval (CI) = 1.08-1.28). Further analysis indicated that the risk allele of rs7529070 (G allele) is in complete linkage disequilibrium (LD) (r2 = 1) with the G allele of rs4648889, which is known to be associated with increased RUNX3 expression. Bioinformatic analysis with existing expression data showed that the expression of RUNX3 is significantly increased in PBC patients (p = 0.001) and the expression level is correlated with disease severity. Consistently, we also found significantly increased RUNX3 expression (p < 0.01) in the livers of dnTGFßRII mice (a PBC mouse model). This study suggests that the RUNX3 locus may associate with PBC in Han Chinese.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33119798

RESUMO

Immunotherapy based on γδT cells has limited efficiency in solid tumors, including colon cancer (CC). The immune evasion of tumor cells may be the main cause of the difficulties of γδT cell-based treatment. In the present study, we explored whether and how B7-H3 regulates the resistance of CC cells to the cytotoxicity of Vγ9Vδ2 (Vδ2) T cells. We observed that B7-H3 overexpression promoted, while B7-H3 knockdown inhibited, CC cell resistance to the killing effect of Vδ2 T cells in vitro and in vivo. Mechanistically, we showed that B7-H3-mediated CC cell resistance to the cytotoxicity of Vδ2 T cells involved a molecular pathway comprising STAT3 activation and decreased ULBP2 expression. ULBP2 blockade or knockdown abolished the B7-H3 silencing-induced increase in the cytotoxicity of Vδ2 T cells to CC cells. Furthermore, cryptotanshinone, a STAT3 phosphorylation inhibitor, reversed the B7-H3 overexpression-induced decrease in ULBP2 expression and attenuated the killing effect of Vδ2 T cells on CC cells. Moreover, there was a negative correlation between the expression of B7-H3 and ULBP2 in the tumor tissues of CC patients. Our results suggest that the B7-H3-mediated STAT3/ULBP2 axis may be a potential candidate target for improving the efficiency of γδT cell-based immunotherapy in CC.

9.
Cell Death Dis ; 11(10): 824, 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33011740

RESUMO

As an important modality for the local control of colorectal cancer (CRC), radiotherapy or neoadjuvant radiotherapy is widely applied in the clinic, but radioresistance has become a major obstacle for CRC radiotherapy. Here we reported that B7-H3, an important costimulatory molecule, is associated with radioresistance in CRC. The expression of B7-H3 was obviously increased in CRC cells after irradiation. The enhanced expression of B7-H3 promoted, while the knockdown of B7-H3 inhibited, colony formation and cell activity in CRC cells following radiation treatment. B7-H3 overexpression reduced S phase arrest and protected cell apoptosis induced by radiation, whereas B7-H3 knockdown had the opposite effects. In addition, B7-H3 blockade by 3E8, a specific B7-H3 antibody, significantly sensitized CRC cells to irradiation in vivo. Mechanistic analysis revealed that B7-H3 regulated KIF15 via RNA sequencing, which was in dependent of NF-κB pathway. And small interfering RNA (siRNA)-mediated KIF15 silencing or KIF15 blockade by the inhibitor SB743921 abolished the effect of B7-H3 on radioresistance in vitro and in vivo. Similar to B7-H3, we find that the protein expression levels of KIF15, which showed a positive correlation with B7-H3, was abnormal upregulated in cancer tissues than in adjacent normal tissues and associated with TNM stage. Finally, B7-H3/KIF15 enhanced resistance against irradiation in CRC cells via activating ERK1/2 signaling, a key pathway involved in radioresistance in cancer. Our findings reveal an alternative mechanism by which CRC cells can acquire radioresistance via the B7-H3/KIF15/ERK axis.

10.
BMC Gastroenterol ; 20(1): 306, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32957915

RESUMO

BACKGROUND: Choledochal cysts are divided into 5 types. Physicians believe that Caroli disease (which refers to type V biliary cysts) is a special type of biliary cyst caused by a mutation in the PKHD1 gene and is associated with autosomal recessive polycystic kidney disease (ARPKD). There is currently no clear association between other types of choledochal cysts and polycystic kidney disease. CASE PRESENTATION: We report a 65-year-old male patient with jaundice, decreased appetite, and itchy skin. His biochemistry test results indicated obstructive jaundice disease. Cross-sectional imaging showed a type IVA choledochal cyst accompanied by autosomal dominant polycystic kidney disease (ADPKD). Due to economic difficulties, the patient achieved percutaneous transhepatic cholangial drainage (PTCD) instead of surgery. CONCLUSION: To our knowledge, this is the second case report of the coexistence of type IVA choledochal cysts and ADPKD. We conclude that it is vital to be aware that the above condition is a possibility. This case report will aid earlier diagnosis and management and possibly prevent further damage to liver and kidney function.

11.
Oncol Lett ; 20(4): 106, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32831925

RESUMO

Parvimonas micra (P. micra) is reported to be associated with colorectal cancer (CRC). However, its association with colorectal adenoma (CRA) and its role in the initiation of colorectal tumors remain unknown. The present study aimed to clarify the relationship between P. micra and CRA and CRC by exploring the changes of P. micra abundance in an adenoma-carcinoma sequence in a new cohort and 4 public sequencing datasets. To investigate the alterations of P. micra abundance in the gut along the adenoma-carcinoma sequence, quantitative PCR (qPCR) was conducted to measure the relative abundance of P. micra in fecal samples from 277 subjects (128 patients with CRA, 66 patients with CRC and 83 healthy individuals, as controls) who underwent colonoscopy as outpatients. Then, the relative abundance of P. micra was analyzed in fecal samples from 596 subjects (185 healthy controls, 158 CRC, 253 CRA) in four public 16S rRNA sequencing datasets. The qPCR results demonstrated that the CRA group had an abundance of P. micra (P=0.2) similar to that of the healthy control group, while the CRC group had a significantly increased abundance (P=8.2×10-11). The level of P. micra effectively discriminated patients with CRC from healthy controls, while it poorly discriminated patients with CRA from healthy controls; with an area under the receiver operating characteristic curve of 0.867 for patients with CRC and 0.554 for patients with CRA. The same pattern of the alteration of P. micra abundance, which was low in healthy controls and patients with CRA but elevated in patients with CRC, was found in all four public sequencing datasets. These results suggested that P. micra was closely associated with, and may serve as a diagnostic marker for, CRC but not CRA. Moreover, it was indicated that P. micra may be an opportunistic pathogen of CRC, which may promote CRC development but serve a limited role in tumorigenesis.

12.
Cell Death Dis ; 11(8): 651, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32811812

RESUMO

We previously discovered that rs7911488T>C in pre-miR-1307 was closely correlated to the risk of colorectal cancer (CRC). However, the roles of rs7911488 in CRC are still largely unknown. Here we explored the roles of rs7911488 in the growth and metastasis of CRC. We firstly generated cell lines SW480-T and SW480-C for stable expression of rs7911488 T-allelic and C-allelic pre-miR-1307, respectively. We subcutaneously grafted the cells into nude mice. We found that SW480-T tumors with high expression of miR-1307 obviously grew faster than the SW480-C tumors. Moreover, liver metastases (5/8) were observed in the mice bearing SW480-T tumors but not the SW480-C tumor-bearing mice. The results from colony formation assays, transwell assays, and wound healing assays demonstrated that the proliferative and metastatic abilities of SW480-T cells were evidently more potent than the SW480-C cells. Then we utilized gene array, real-time PCR, western blotting, and dual-luciferase reporter assays to figure out that miR-1307 directly inhibited PPRX1 expression by binding to its 3'-UTR. Thereafter, we confirmed that the proliferative and metastatic abilities of SW480 and HCT-116 cells were markedly enhanced by miR-1307, but were suppressed by PRRX1. Moreover, the regulatory roles of miR-1307 in the proliferation and metastasis of CRC cells were reversed by PRRX1. Notably, we also found that PRRX1 repressed CRC tumor growth in nude mice. In summary, our current study revealed that rs7911488-T allele led to over-expression of miR-1307, which inhibited PRRX1 and consequently promoted the proliferation and migration of CRC cells. This might offer a novel insight into the progression of CRC.

13.
Artigo em Inglês | MEDLINE | ID: mdl-32719950

RESUMO

B7-H3, an important co-inhibitor, is abnormally highly expressed in a variety of malignancies. The antibodies targeting B7-H3 have exhibited beneficial therapeutic effects in clinical trials. Therefore, discovery of the regulatory factors in B7-H3 expression may provide new strategies for tumor therapy. Here, we investigated the splicing factors involved in the splicing of B7-H3. By individual knockdown of the splicing factors in colorectal cancer (CRC) cells, we found that B7-H3 expression was markedly inhibited by SRSF3 and SRSF8, especially SRSF3. Then we found that both SRSF3 and B7-H3 were highly expressed in CRC tissues. Moreover, high-expression of either SRSF3 or B7-H3 was significantly correlated with poor prognosis of patients. The expression of B7-H3 mRNA and protein were evidently reduced by SRSF3 silence, but were enhanced by overexpression of SRSF3 in both HCT-116 and HCT-8 cells. The results from the RNA immunoprecipitation (RIP) assays demonstrated that SRSF3 protein directly binds to B7-H3 mRNA. In addition, we constructed a minigene recombinant plasmid for expressing B7-H3 exons 3-6. We found that SRSF3 contributed to the retention of B7-H3 exon 4. These findings demonstrate that SRSF3 involves in the splicing of B7-H3 by directly binding to its exon 4 and/or 6. It may provide novel insights into the regulatory mechanisms of B7-H3 expression and potential strategies for the treatment of CRC.

14.
Dig Liver Dis ; 52(10): 1195-1200, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32505571

RESUMO

BACKGROUND: TRAIL is best known for killing cancer cells selectively, however, some cancers resist TRAIL treatment for various reasons. Esophageal adenocarcinoma is such an example. Previously, we reported that the tumor cells interrupted TRAIL-mediated apoptosis by overexpressing the decoy receptors and survivin. AIMS: To investigate TRAIL resistance in esophageal adenocarcinoma during GERD. METHODS: We simulated GERD episodes in vitro by exposing cancer cells to the acid/bile conditions acutely as well as chronically. TRAIL and its receptors were examined for expression, interaction, and induction of cell death. RESULTS: We found that acid/bile exposure drove the tumor cells to express TRAIL and TRAILR2 robustly, but did not lead to apoptosis, because the tumor cells overexpressed TRADD to replace FADD as the adaptor molecule to trigger NFκB activation instead of caspases, and thereby convert a death signal from TRAIL into a stimulus for survival. The tumor cells also overexpressed c-FLIP to keep caspases away from TRAILR2 in case FADD finds a way back to the death receptor. CONCLUSION: Multiple reasons contribute to TRAIL resistance in esophageal adenocarcinoma, including overexpression of the decoy receptors to block the death receptors, using TRADD to replace FADD, and using c-FLIP to replace caspase-8.

15.
Oncoimmunology ; 9(1): 1748991, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32363121

RESUMO

The immunoregulatory protein B7-H3, a member of the B7 family, has been confirmed to be highly expressed in colon cancer. However, the exact influence of B7-H3 on the features and antitumor ability of γδT cells in colon cancer remains unknown. In the present study, we investigated that the proportions of B7-H3+ γδT cells were distinctly increased in the peripheral blood and tumor tissues of colon cancer patients. B7-H3 blockade or knockdown promoted proliferation, inhibited cell apoptosis and induced the expression of activation markers (CD25 and CD69) on Vδ2 T cells. In contrast, treatment with the B7-H3 agonist 4H7 had the opposite effect. Furthermore, B7-H3 suppressed IFN-γ expression by inhibiting T-bet in Vδ2 T cells. Moreover, B7-H3 mediated the inhibition of Vδ2 T cell cytotoxicity via the downregulation of IFN-γ and perforin/granzyme B expression. More importantly, blocking the B7-H3 function significantly enhanced the cytotoxicity of Vδ2 T cells against colon cancer cells in vivo. Therefore, the inhibition or blockade of B7-H3 is a potential immunotherapeutic approach for colon cancer.

16.
Gene ; 750: 144753, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32376451

RESUMO

Gastric cancer (GC) is a common malignant tumor having poor prognosis globally. Circular RNA (circRNA) is a circular endogenous RNA generated by special selective splicing that occurs in various traits. Studies show that hsa_circ_0017639 is abnormally expressed and involved in tumorigenesis. Nevertheless, the hsa_circ_0017639 role in GC is unknown. This study detected hsa_circ_0017639 expression in a GC cell line using RT-qPCR. Subcellular localization of hsa_circ_0017639 was verified via FISH. We assessed correlations amongst miRNA, hsa_circ_0017639 and relative protein levels using luciferase reporter assays and RNA pulldown assays. The data illustrated that in hsa_circ_assays, expression was enhanced in GC cell. Downregulation of hsa_circ_0017639 decreased GC cell proliferation and migration in in vitro and in vivo experiments. RNA pulldown and RT-qPCR analysis verified that hsa_circ_0017639 sponged miR-224-5p. Bioinformatic and luciferase reporter assays validated that miR-224-5p and USP3 were downstream targets of hsa_circ_0017639. Upregulation of USP3 or downregulation of miR-224-5p restored proliferation and migration by MKN-28 and MGC-803 cells after hsa_circ_0017639 silencing. Upregulation of USP3 restored MKN-28 and MGC-803 cell proliferation and migration after overexpression of miR-224-5p. Our collective findings advised that hsa_circ_0017639 takes part in GC progression through regulating the miR-224-5p/USP3 axis, highlighting its potential as an effective GC therapeutic target.


Assuntos
MicroRNAs/biossíntese , RNA Circular/metabolismo , Neoplasias Gástricas/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica , RNA Circular/biossíntese , RNA Circular/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ativação Transcricional , Proteases Específicas de Ubiquitina/genética , Regulação para Cima
17.
Iran J Immunol ; 17(1): 52-63, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32224541

RESUMO

BACKGROUND: Tim-3 has been considered as an ideal target for the immunotherapy of inflammation, but it is unclear whether Tim-3 also plays an important role in acute pancreatitis (AP), as well. OBJECTIVE: To identify the immunomodulatory effects and mechanisms of Tim-3 action in the early stages of severe acute pancreatitis in mice. METHODS: Male BALB/c mice were randomly divided into sham injection group, severe acute pancreatitis group, and anti-Tim-3 treated group. Histopathological scores of the pancreas were calculated, pancreatic myeloperoxidase (MPO) activity was assessed. The concentrations of serum IL-6, IL-10, and TNF-α were evaluated by ELISA method. Quantitative RT-PCR was performed to detect the transcripts of Tim-3, IL-6, IL-10, TNF-α, and TLR4 in peritoneal macrophages. The levels of peritoneal macrophages Tim-3, TLR4, MyD88, and NF-kB p65 were measured by western blot analysis. RESULTS: The pathological scores of the anti-Tim-3 treated group (11.5 ± 1.3) significantly increased compared with the sham (1.3 ± 0.5) and SAP groups (6.9 ± 1.0). Furthermore, the downregulation of Tim-3 significantly aggravated mouse pancreatic tissue damage. It was further shown that Tim-3 negatively regulated the production of pro-inflammatory cytokines, IL-6 and TNF-α, as well as anti-inflammatory cytokine IL-10. Of note, the negative regulation of inflammatory cytokines by Tim-3 was mediated by the activation of TLR4/MyD88 NF-kB signaling pathway. CONCLUSION: Our study showed that Tim-3 might play an important role in the development of AP through regulating the inflammatory response.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A/imunologia , Pancreatite/imunologia , Pancreatite/patologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C
18.
J Cancer ; 11(8): 2158-2170, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32127943

RESUMO

Colorectal cancer (CRC) is one of the most common malignancies, and chemoresistance is one of the key obstacles in the clinical outcome. Here, we studied the function of B7-H3 in regulating cell cycle-mediated chemoresistance in CRC. The ability of B7-H3 in regulating chemoresistance was investigated via cell viability, clonogenicity, apoptosis and cycle analysis in vitro. Moreover, the role of B7-H3/CDC25A axis in regulating chemoresistance in vivo in the xenograft tumor models by intraperitoneal injection of oxaliplatin (L-OHP) and CDC25A inhibitors. The correlation between B7-H3 and CDC25A was examined in the CRC patients by immunohistochemistry (IHC) and pathological analyses. We found that B7-H3 could effectively enhance the resistance to a chemotherapeutic drug (oxaliplatin or 5-fluorouracil) via CDC25A. B7-H3 regulated the expression of CDC25A by the STAT3 signaling pathway in CRC cells. Furthermore, overexpression of B7-H3 enhanced chemoresistance by reducing the G2/M phase arrest in a CDC25A-dependent manner. Silencing CDC25A or treatment with CDC25A inhibitor could reverse the B7-H3-induced chemoresistance of cancer cells. Moreover, both B7-H3 and CDC25A were significantly upregulated in CRC samples compared with normal adjacent tissues and that the levels correlated with tumor stage. CDC25A was positively correlated with B7-H3 expression in this cohort. Taken together, our findings provide an alternative mechanism by which CRC cells can acquire chemoresistance via the B7-H3/CDC25A axis.

19.
Cell Death Dis ; 11(1): 55, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974361

RESUMO

Tumor angiogenesis is a hallmark of cancer and is involved in the tumorigenesis of solid tumors. B7-H3, an immune checkpoint molecule, plays critical roles in proliferation, metastasis and tumorigenesis in diverse tumors; however, little is known about the biological functions and molecular mechanism underlying B7-H3 in regulating colorectal cancer (CRC) angiogenesis. In this study, we first demonstrated that the expression of B7-H3 was significantly upregulated and was positively associated with platelet endothelial cell adhesion molecule-1 (CD31) level in tissue samples from patients with CRC. In addition, a series of in vitro and in vivo experiments showed that conditioned medium from B7-H3 knockdown CRC cells significantly inhibited the migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs), whereas overexpression of B7-H3 had the opposite effect. Furthermore, B7-H3 promoted tumor angiogenesis by upregulating VEGFA expression. Recombinant VEGFA abolished the inhibitory effects of conditioned medium from shB7-H3 CRC cells on HUVEC angiogenesis, while VEGFA siRNA or a VEGFA-neutralizing antibody reversed the effects of conditioned medium from B7-H3-overexpressing CRC cells on HUVEC angiogenesis. Moreover, we verified that B7-H3 upregulated VEGFA expression and angiogenesis by activating the NF-κB pathway. Collectively, our findings identify the B7-H3/NF-κB/VEGFA axis in promoting CRC angiogenesis, which serves as a promising approach for CRC treatment.

20.
J Exp Med ; 217(1)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31645367

RESUMO

Core 1-derived mucin-type O-glycans (O-glycans) are a major component of gastric mucus with an unclear role. To address this, we generated mice lacking gastric epithelial O-glycans (GEC C1galt1-/-). GEC C1galt1-/- mice exhibited spontaneous gastritis that progressed to adenocarcinoma with ∼80% penetrance by 1 yr. GEC C1galt1-/- gastric epithelium exhibited defective expression of a major mucus forming O-glycoprotein Muc5AC relative to WT controls, which was associated with impaired gastric acid homeostasis. Inflammation and tumorigenesis in GEC C1galt1-/- stomach were concurrent with activation of caspases 1 and 11 (Casp1/11)-dependent inflammasome. GEC C1galt1-/- mice genetically lacking Casp1/11 had reduced gastritis and gastric cancer progression. Notably, expression of Tn antigen, a truncated form of O-glycan, and CASP1 activation was associated with tumor progression in gastric cancer patients. These results reveal a critical role of O-glycosylation in gastric homeostasis and the protection of the gastric mucosa from Casp1-mediated gastric inflammation and cancer.


Assuntos
Gastrite/metabolismo , Mucinas/metabolismo , Polissacarídeos/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Antígenos Glicosídicos Associados a Tumores/metabolismo , Carcinogênese/metabolismo , Caspase 1/metabolismo , Feminino , Mucosa Gástrica/metabolismo , Glicosilação , Homeostase/fisiologia , Humanos , Inflamação/metabolismo , Masculino , Camundongos , Muco/metabolismo , Neoplasias/metabolismo
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