Colorectal cancer-associated fibroblasts promote metastasis by up-regulating LRG1 through stromal IL-6/STAT3 signaling

Cancer-associated fibroblasts (CAFs) have been shown to play a strong role in colorectal cancer metastasis, yet the underlying mechanism remains to be fully elucidated. Using CRC clinical samples together with ex vivo CAFs-CRC co-culture models, we found that CAFs induce expression of Leucine Rich Alpha-2-Glycoprotein 1(LRG1) in CRC, where it shows markedly higher expression in metastatic CRC tissues compared to primary tumors. We further show that CAFs-induced LRG1 promotes CRC migration and invasion that is concomitant with EMT (epithelial-mesenchymal transition) induction. In addition, this signaling axis has also been confirmed in the liver metastatic mouse model which displayed CAFs-induced LRG1 substantially accelerates metastasis. Mechanistically, we demonstrate that CAFs-secreted IL-6 (interleukin-6) is responsible for LRG1 up-regulation in CRC, which occurs through a direct transactivation by STAT3 following JAK2 activation. In clinical CRC tumor samples, LRG1 expression was positively correlated with CAFs-specific marker, α-SMA, and a higher LRG1 expression predicted poor clinical outcomes especially distant metastasis free survival, supporting the role of LRG1 in CRC progression. Collectively, this study provided a novel insight into CAFs-mediated metastasis in CRC and indicated that therapeutic targeting of CAFs-mediated IL-6-STAT3-LRG1 axis might be a potential strategy to mitigate metastasis in CRC.Subject terms: Colon cancer, Cancer microenvironment     

The combination of arbuscular mycorrhizal fungi inoculation (Glomus versiforme) and 28‐homobrassinolide spraying intervals improves growth by enhancing photosynthesis,nutrient absorption,and antioxidant system in cucumber (Cucumis sativus L.) under salinity

Salinity is one of the major obstacles in the agriculture industry causing huge losses in productivity. Several strategies such as plant growth regulators with arbuscular mycorrhizal fungi (AMF) have been used to decrease the negative effects of salt stress. In our experiment, 28‐homobrassinolide (HBL) with spraying intervals was combined with AMF (Glomus versiforme) in cucumber cultivars Jinyou 1^# (salt sensitive) and (Changchun mici, in short, CCMC, salt tolerant) under NaCl (100 mmol/L). Studies have documented that the foliar application of HBL and AMF colonization can enhance tolerance to plants under stress conditions. However, the mechanism of the HBL spraying intervals after 15 and 30 days in combination with AMF in cucumber under salt stress is still unknown. Our results revealed that the HBL spraying interval after 15 days in combination with AMF resulted in improved growth, photosynthesis, and decreased sodium toxicity under NaCl. Moreover, the antioxidant enzymes SOD (superoxide dismutase; EC 1.15.1.1) and POD activity (peroxidase; EC 1.11.1.7) showed a gradual increase after every 10 days, while the CAT (catalase; EC 1.11.1.6) increased after 30 days of salt treatments in both cultivars. This research suggests that the enhanced tolerance to salinity was mainly related to elevated levels of antioxidant enzymes and lower uptake of Na⁺, which lowers the risk of ion toxicity and decreases cell membrane damage.     

Dilated cardiomyopathy caused by tissue-specific ablation of SC35 in the heart

Many genetic diseases are caused by mutations in cis-acting splicing signals, but few are triggered by defective trans-acting splicing factors. Here we report that tissue-specific ablation of the splicing factor SC35 in the heart causes dilated cardiomyopathy (DCM). Although SC35 was deleted early in cardiogenesis by using the MLC-2v-Cre transgenic mouse, heart development appeared largely unaffected, with the DCM phenotype developing 3-5 weeks after birth and the mutant animals having a normal life span. This nonlethal phenotype allowed the identification of downregulated genes by microarray, one of which was the cardiac-specific ryanodine receptor 2. We showed that downregulation of this critical Ca2+ release channel preceded disease symptoms and that the mutant cardiomyocytes exhibited frequency-dependent excitation-contraction coupling defects. The implication of SC35 in heart disease agrees with a recently documented link of SC35 expression to heart failure and interference of splicing regulation during infection by myocarditis-causing viruses. These studies raise a new paradigm for the etiology of certain human heart diseases of genetic or environmental origin that may be triggered by dysfunction in RNA processing.     

Oxidative mechanisms involved in kainate-induced cytotoxicity in cortical neurons

In our previous experiments, evidence of free radical formation has been demonstrated in gerbil brain after kainic acid (KA) administration. In the present study, the mechanisms involved in KA-induced free radical formation and subsequent cell degeneration were investigated using high density cortical neuron cultures. A free radical trapping agent,a-phenyl-N-tert-butyl-nitrone (PBN), as well as the combined action of superoxide dismutase and catalase attenuated KA neurotoxic effect. Calpain-induced xanthine oxidase (XO) activation may play an important role in KA excitotoxicity since calpain inhibitor I as well as allopurinol, a selective XO inhibitor, significantly protected the cortical neurons from KA-induced cell death. However, XO activation may not be the only source producing free radicals, other free radical generating systems such as nitric oxide synphase may also play a role in KA insult.