Background. Postoperative abdominal adhesion remains one of the frequent complications after abdominal surgery and lacks effective intervention. Peritoneal mesothelial cell injury and healing play crucial roles in the process of adhesion formation, and identifying this mechanism might provide new insight into possible new therapeutic strategies for this disease. Transmembrane and immunoglobulin domain-containing 1 (TMIGD1) has been proven to protect renal epithelial cells from injury induced by oxidative stress and has also been identified as a novel adhesion molecule. Here, we investigated the role of TMIGD1 and its possible mechanism in adhesion formation. Materials and Methods. Immunohistochemistry (IHC), qPCR, and immunofluorescence (IHF) were used to detect the expression of TMIGD1. The grade and tenacity score of adhesion were used to evaluate the adhesion formation conditions. A TMIGD1-overexpressing HMrSV5 cell line was established. MTT assay, Western blotting, Annexin V apoptosis analysis, and CK19 staining were used to measure mesothelial cell viability, apoptosis, and completeness. ROS and MDA detection were used to measure mesothelial cell oxidative stress levels. JC-1 staining, IHF, and transmission electron microscopy were performed to assess mitochondrial function. Scratch-wound and adhesion assays were used to evaluate the adhesion ability of mesothelial cells. Results. First, we showed that TMIGD1 was decreased in mouse abdominal adhesion tissue and peritoneal mesothelial cells. Second, TMIGD1 overexpression inhibited adhesion formation. Third, TMIGD1 overexpression protected mesothelial cells from hydrogen peroxide- (H2O2-) induced oxidative stress injury. Fourth, TMIGD1 overexpression alleviated oxidative stress by protecting the mitochondrial function of mesothelial cells. In addition, TMIGD1 overexpression enhanced mesothelial cell adhesion. Conclusion. Our findings suggest that TMIGD1 protects mesothelial cells from oxidative stress injury by protecting their mitochondrial function, which is decreased in regular abdominal adhesion tissue. In addition, TMIGD1 enhances peritoneal mesothelial cell adhesion to promote healing.
Adenomatous polyposis coli (APC) and KRAS proto-oncogene (KRAS) mutations frequently co-occur in non-small cell lung cancer. Inactivating APC mutations in colorectal carcinoma has been well characterized, leading to the approaches targeting on dysregulated APC pathway. However, it remains undetermined whether such approaches are also applicable to non-small cell lung cancer patients harboring similar mutations of APC. Dickkopf-related protein 2 (DKK2) is a Wnt antagonist. Our previous study has proved that anti-DKK2 antibody 5F8 suppressed the growth of colorectal carcinoma with APC mutations, illustrating a new target agent of APC-mutated tumors. This study aimed to investigate the potential of applying anti-DKK2 antibody to non-small cell lung cancer with APC mutations. We found significant upregulation of Dkk2 expression in APC-mutated lung cancers. Administration of DKK2 antibody inhibited cancer growth via modulating tumor immune microenvironment in lung cancer mouse models. Our study provided strong evidence supporting APC mutations-directed applications of anti-DKK2 targeted therapy in a wide range of cancer types, including lung cancer.
BackgroundMetastatic recurrence remains a major cause of colorectal cancer (CRC) mortality. In this study, we focused on the role and the potential underlying mechanisms of nuclear factor of activated T cells 1 (NFATc1) in CRC metastasis.
MethodsWe examined the expression of NFATc1 in 140 cases of CRC tissues and 35 corresponding adjacent tissues, as well as analyzed the correlation between NFATc1 expression levels and clinical stages. The role of NFATc1 in CRC metastasis and the molecular mechanisms were investigated in both in vitro and in vivo models.
ResultsThe results showed that NFATc1 expression was increased in metastatic CRC tissues and positively associated with clinical stages (Stage I vs. Stage II, III or IV) of CRC. Overexpression of NFATc1 promoted CRC cell migration, invasion and epithelial-mesenchymal transition (EMT). Moreover, SNAI1 was veri ed as the direct transcriptional target of NFATc1 and interacted with Slug to promote EMT. Remarkably, our lung and liver double metastasis mouse model demonstrated that NFATc1 overexpression accelerated CRC metastasis, and treatment with FK506, a calcineurin-NFAT pathway inhibitor, could suppress CRC metastasis in vivo.
ConclusionsTaken together, our ndings suggest that NFATc1 could transcriptionally activate SNAI1, which in turn could interact with Slug to mediate EMT and to promote CRC metastasis, making NFATc1 a promising target in CRC treatment.
There are limited options for targeted therapies for colorectal cancer (CRC). Anti-EGFR therapy is limited to CRC without KRAS mutations. Even worse, most of CRC are refractory to currently immune checkpoint blockade. DKK2, which is upregulated in CRC, was recently found to suppress host immune responses, and its blockage effectively impeded tumor progression in benign genetic CRC models in our previous study. Here, our recent study demonstrated that in human CRC tumor samples expressing high levels of DKK2, DKK2 blockade caused stronger activation of tumor infiltrating CD8
+
T cells in
ex vivo
culture. Intriguingly, we observed a correlation of high DKK2 expression with increased lymph node metastasis prevalence in these CRC patients as well. Furthermore, in a mouse genetic CRC model with mutations in APC and KRAS, which more closely mimics advanced human CRC, we confirmed the tumor inhibitory effect of DKK2 blockade, which significantly retarded tumor progression and extended survival, with increased immune effector cell activation and reduced angiogenesis. Based on this, we performed a combined administration of DKK2 blockade with sub-optimal anti-VEGFR treatment and observed a synergetic effect on suppressing tumor angiogenesis and progression, as well as extending survival, better than those of every single therapy. Thus, this study provides further evidence for the potential therapeutic application of DKK2 blockade in the clinical treatment of human CRC.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.