Fibronectin 1 (FN1) is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, metastasis, and implicated in various biochemical processes. However, its effects on the development and progression of human cancer, especially colorectal cancer (CRC), are unclear. To evaluate the relationship between the expression of FN1 and the histopathologic parameters of patients with CRC or the proliferation, migration, and invasion of colorectal cancer cell lines, we screened FN1 as a new candidate gene which promotes development of CRC, in an independent dataset (The Human Protein Atlas website). Here, we reported that FN1 was elevated in CRC tissues compared with normal colon tissues. Further, FN1 expression level was correlated with age, lymph vascular invasion, and survival rate. Knockdown of FN1 in two CRC cell lines, LOVO, and SW1116, significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis. Western blot analysis showed that down-regulation of FN1 significantly decreased the expression of Bcl-2, MMP-9, Twist, and increased the expression of Bax, Caspase-3, and E-cadherin in LOVO and SW1116 cells. Then, we found that the protein ITGA5 was identified as a binding partner of FN1 and ITGA5 overexpression reversed FN1-induced tumorigenesis of CRC in vitro. Taken together, FN1 suppressed apoptosis and promoted viability, invasion, and migration in CRC through interacting with ITGA5. FN1 may be a prognostic factor and potential target for CRC treatment.

The mechanisms responsible for radioresistance in pancreatic cancer have yet to be elucidated, and the suppressive tumor immune microenvironment must be considered. We investigated whether the radiotherapy-augmented Warburg effect helped myeloid cells acquire an immunosuppressive phenotype, resulting in limited treatment efficacy of pancreatic ductal adenocarcinoma (PDAC). Radiotherapy enhanced the tumor-promoting activity of myeloid-derived suppressor cells (MDSC) in pancreatic cancer. Sustained increase in lactate secretion, resulting from the radiation-augmented Warburg effect, was responsible for the enhanced immunosuppressive phenotype of MDSCs after radiotherapy. Hypoxia-inducible factor-1α (HIF-1α) was essential for tumor cell metabolism and lactate-regulated activation of MDSCs via the G protein-coupled receptor 81 (GPR81)/mTOR/HIF-1α/STAT3 pathway. Blocking lactate production in tumor cells or deleting Hif-1α in MDSCs reverted antitumor T-cell responses and effectively inhibited tumor progression after radiotherapy in pancreatic cancer. Our investigation highlighted the importance of radiation-induced lactate in regulating the inhibitory immune microenvironment of PDAC. Targeting lactate derived from tumor cells and the HIF-1α signaling in MDSCs may hold distinct promise for clinical therapies to alleviate radioresistance in PDAC.

The glucocorticoid receptor is a member of the nuclear receptor family that controls many distinct gene networks, governing various aspects of development, metabolism, inflammation, and the stress response, as well as other key biological processes in the cardiovascular system. Recently, research in both animal models and humans has begun to unravel the profound complexity of glucocorticoid signaling and convincingly demonstrates that the glucocorticoid receptor has direct effects on the heart and vessels in vivo and in vitro. This research has contributed directly to improving therapeutic strategies in human disease. The glucocorticoid receptor is activated either by the endogenous steroid hormone cortisol or by exogenous glucocorticoids and acts within the cardiovascular system via both genomic and non-genomic pathways. Polymorphisms of the glucocorticoid receptor are also reported to influence the progress and prognosis of cardiovascular disease. In this review, we provide an update on glucocorticoid signaling and highlight the critical role of this signaling in both physiological and pathological conditions of the cardiovascular system. With increasing in-depth understanding of glucocorticoid signaling, the future is promising for the development of targeted glucocorticoid treatments and improved clinical outcomes.