Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma

The well-known insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R) signaling pathway is overexpressed in many tumors, and is thus an attractive target for cancer treatment. However, results have often been disappointing due to crosstalk with other signals. Here, we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma (HCC) cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) activity. In response to ligand binding, IGF-1Rβ is translocated into the ER by β-arrestin2 (β-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβ levels. ER IGF-1Rβ phosphorylates SERCA2 on Tyr990 to enhance its activity. Mutation of SERCA2-Tyr990 disrupted the interaction of ER IGF-1Rβ with SERCA2, and therefore ER IGF-1Rβ failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca2+ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rβ and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca2+ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr990 in HCC.

Activation of insulin-like growth factor-1 receptor (IGF-1R) promotes growth of colorectal cancer through triggering the MEX3A-mediated degradation of RIG-I

Insulin-like growth factor-1 receptor (IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers. However, targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings. Here, we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I. The active β-arrestin-2 scaffolds this disobliging signaling to talk with MEX3A. In response to ligands, IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250, opening the middle loop (Leu130‒Cys141) to the RING domain of MEX3A through the conformational changes of βarr2. The models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I. The assay of the mutants βarr2Y64A and βarr2Y250A further confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of MEX3A. The truncated-βarr2 and the peptide ATQAIRIF, which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes, thus blocking the IGF-1R-triggered RIG-I degradation. Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway. Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I. In summary, we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.

Correlation between macular thickness and course of disease, blood glucose level in patients with diabetic retinopathy without diabetes mellitus / 眼科新进展

Objective To analyze the difference of macular retinal thickness between normal subjects and diabetic patients without retinopathy,and discuss the relationship between macular thickness and the course of diabetes,blood glucose level.Methods Twenty-two cases of patients with diabetic without retinopathy without retinopathy in our hospital of fourth Department of Internal medicine from April 2016 to November 2016 were selected as diabetic without retinopathy group,and another 22 normal pemons were selected as the normal group.The central subfield retinal thickness (CSRT),cube volume(CV) and cube average thickness(CAT) of all patients were determined by optical coherence tomography (OCT),and the difference of CSRT,CV and CAT between diabetic patients and normal group were analyzed.Then,the patients with diabetic retinopathy were sub-grouped according to the course of diabetes (group A,B,C,) and blood glucose status (group D and E),and the differences of CSRT,CV and CAT among them were compared.Results With the increase of diabetes duration in the diabetic without retinopathy group,CSRT,CV and CAT were gradually increased,and there was significant difference (P ＜ 0.05).With rising blood sugar in diabetics in the diabetic without retinopathy group,CSRT,CV and CAT were gradually increased,and there was significant difference (P ＜ 0.05).There were positive correlation between CSRT,CV,CAT and course,blood sugar of diabetes mellitus (all P ＜ 0.05).Conclusion Compared with normal population,CSRT,CV and CAT are significantly thickened in diabetes mellitus patients,and CSRT,CV and CAT are increased gradually with the increase of diabetes and blood glucose,which provide reliable reference for the diagnosis of early diabetic retinopathy.

Association of CDKN2B-AS1 rs1333049 with Brain Diseases: A Case-control Study and a Meta-analysis

OBJECTIVE: CDKN2B-AS1 polymorphisms were shown to associate with the risk of stroke in European. The goal of this study was to evaluate the contribution of CDKN2B-AS1 rs1333049 to the risk of hemorrhagic stroke (HS) and brain tumor (BT) in Han Chinese. METHODS: A total of 142 HSs, 115 BTs, and 494 controls were included in the current association study. The genotyping test was performed using the melting temperature shift method. RESULTS: We failed to validate the association of CDKN2B-AS1 rs1333049 with the risk of brain disease. Significantly higher levels of low-density lipoprotein cholesterol (LDL-C) (p=0.027), high-density lipoprotein cholesterol (HDL-C) (p0.05). The meta-analysis of 10 studies among 133,993 individuals concluded that rs1333049 of CDKN2B-AS1 gene was likely to increase a 16% incidence rate of cerebrovascular disease (CD) among various populations (odds ratio 1.16, 95% confidence interval 1.08–1.25; p<0.0001, random-effect method). CONCLUSION: Our case-control study identified rs1333049 genotypes showed different association with the concentration of the LDL-C, HDL-C and TC in the HS patients. Meta-analysis supported the association between rs1333049 and CD risk in various populations, although we were unable to observe association between rs1333049 and the risk of HSs in Han Chinese.

Clinical study of intraperitoreal immune chemotherapy for colorectal cancer following radical operation / 中国基层医药

Objective To Research the efficacy and side effects of intra-abdominal chemotherapy immune to the abdominal cavity after colorectal cancer liver metastasis and local recurrence.Methods 172 eases of colorectal cancer patients after radical operation were randomly divided into conventional regulation 86 cases of abdominal chemotherapy group(control group) and the immune abdominal chemotherapy group of 86 cases(observation group).The control group received 5-FU1.0,MMC8mg intraperitoneal chemotherapy The observation group at the grass-rcots level to add IL-2 50 million U.Results Observation group effective rate .was 70.9% higher than 55.8% (P ＜0.05) ;the obsenation gionp the three-year survival rate 83.7%,dlsease-free survival rate was 44.2% higher than the 62.8%,22.1% (P＜0.05) ;observation group three-year recurrence rate of 25.6% and 34.9% lower than the rate of liver metastases in the control group of 37.8%,48.9% (P＜0.05) ;two groups of gastrointestinal reaction,ⅠⅡ or degree of bone marrow suppression,liver function mildly abnormal ( elevated alanine amiuotransferase) had no difference.Conclusion For advanced colorectal cancer patients with early immune abdominal chemotherapy,the effective prevention and treatment of abdominal cavity and liver metastasis planting to improve the survival rate,side effects of light,fewer complications,the extension of survival,worthy of clinical application.

Adhesion induces matrix metalloproteinase-9 gene expression in ovarian cancer cells / 中华肿瘤杂志

<p><b>OBJECTIVE</b>This work was conducted to investigate the expression of matrix metalloproteinase 9 (MMP 9) gene in cancer cells by fibronectin adhesion and the underlying mechanism of cell invasion.</p><p><b>METHODS</b>Following adhesion of ovarian cancer cells A2780 to fibronectin, mRNA expression of MMP cells were assayed by reverse transcription-polymerase chain reaction (RT-PCR). MMP9 promoter was cloned from genomic DNA of HT1080 cells with PCR. The MMP-9-pGL2 reporter gene vector was constructed and then transiently transfected into A2780 cells.</p><p><b>RESULTS</b>Adhesion induced the increase of cellular MMP9 mRNA content in A2780 cells, not affecting the expression of MMP2 or TIMP-1 gene. The stimulation was enhanced with the increase adhesion time. When the transfected cells were allowed to adhere and spread on FN-coated surface, the promoter activity of MMP9 gene was also enhanced dramatically.</p><p><b>CONCLUSION</b>Cell-ECM adhesion may stimulate the expression of MMP9 gene through stimulating the promoter activity, thereby enhancing cancer cell invasion and metastasis.</p>