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BACKGROUND: Our recent studies demonstrated that both nintedanib, an FDA-approved quadruple kinase inhibitor, and gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, protect against obstructive kidney disease. It remains unknown whether they have a synergistic effect. METHODS: In this study, we investigated the effect of combined administration of nintedanib and gefitinib on renal fibrosis in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO). RESULTS: Combined treatment with nintedanib and gefitinib after UUO resulted in a greater antifibrotic effect compared with their individual application. Mechanistically, administration of nintedanib blocked UUO-induced phosphorylation of multiple kinase receptors associated renal fibrosis, including platelet-derived growth factor receptors, fibroblast growth factor receptors, vascular endothelial growth factor receptors, and Src family kinase, while gefitinib inhibited EGFR phosphorylation. Their combination also exhibited a more pronounced effect in reducing expression of tissue inhibitors of metalloproteinase-2 (TIMP-2), increasing expression of matrix metalloproteinase-2 (MMP-2), and suppressing renal proinflammatory cytokine expression and macrophage infiltration in the injured kidney. Furthermore, simultaneous administration of nintedanib and gefitinib was more potent in inhibiting UUO-induced renal phosphorylation of signal transducer and activator of transcription-3 (STAT3), nuclear factor-κB, and Smad-3 compared with monotherapy. In cultured renal interstitial fibroblasts, cotreatment with these 2 inhibitors also had synergistic effects in abrogating transforming growth factor ß1-induced activation of renal fibroblasts and phosphorylation of Akt, STAT3, and Smad3. CONCLUSIONS: Combined application of nintedanib and gefitinib has a synergistic antifibrotic effect in the kidney and may hold translational potential for the treatment of chronic kidney disease.
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In recent years, the incidence and mortality rates of colorectal cancer are increasing year by year. With the deepening of molecular biology research and the discovery of driver genes, the treatment of colorectal cancer has gradually developed to the direction of individuation and precision. As the second member of the epidermal growth factor receptor family, human epidermal growth factor receptor 2 (HER2) is involved in the regulation of cell growth, reproduction and division and the control of tumor growth. This article reviews the correlation between expression of HER2 and colorectal cancer.
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Multidisciplinary treatment of rectal cancer and precise surgical strategy and total mesorectal excision(TME) are the basis for effective treatment of rectal cancer.At present,the best scheme of neoadjuvant therapy for rectal cancer has not been established.The neoadjuvant chemotherapy,neoadjuvant short and long range radiotherapy,radiotherapy adverse reaction,the timing of surgery for rectal cancer are summarized as follows.
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Many long non -coding RNA ( lncRNA ) has been found in recent years .The abnormal ln-cRNA expression is closely related to the occurrence and development of tumor .LncRNA can be divided into the tumor promoting and tumor inhibiting according to the function .lncRNA generally overexpresses in solid tumor tis-sue,acts as an important factor involved in tumor invasion ,proliferation and metastasis ,and has been associated with prognosis of neoplasm .This paper describes the current situation of lncRNA research .We mainly introduce several functions of lncRNA which thoroughly researched at present (such as HOTAIR,H19,MALAT-1,Lin-cRNA-p21,GAS5,etc) and their expression in colorectal tumor tissue ,indicating that regulating the expression level of lncRNA may provide a new basis for the diagnosis and treatment of colorectal cancer .
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Objective To explore the associations between polymorphisms in CYP24A1 gene and the risk and prognosis of colorectal cancer ( CRC) .Methods A case-control study consisting of 528 CRC patients and 605 cancer free controls and a follow up study with 317 cases were conducted to explore the associations be-tween two polymorphisms in CYP24A1 and the risk and prognosis of CRC,as well as the combinations and inter-actions of polymorphisms with dietary factors on CRC risk.Results Although there was no association between polymorphisms in CYP24A1 and the risk of CRC,significant combinative effects between polymorphisms and diet-ary factors on CRC risk were observed.For Rs4809957 polymorphism,the prognosis of AA genotype carriers was worse than GG/GA carriers in CRC,colon cancer and rectal cancer(Log-rank test P=0.01,P=0.01,P=0.02,respectively).Compared with GG genotype,AA genotype carriers of Rs4809957 polymorphism had worse prognosis in CRC(HR =2.35,95%CI =1.28~4.30),colon caner(HR =2.37,95% CI =1.09~5.14) and rectal cancer(HR =2.11,95% CI =1.11~4.01).Conclusion The combinations of the polymorphisms in CYP24A1 gene with dietary factors are associated with the susceptibility of CRC,and Rs4809957 polymorphism may lead to a worse prognosis of CRC.
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Objective Inhibitor of growth 1 ( ING1 ) gene has been identified as a novel candidate of tumor suppressor gene .Over-expression of ING1 plays well-established roles in numerous cell processes ,inclu-ding DNA repair and cell apoptosis .Our study is to investigate the clinical significances of expression of ING 1 in colorectal cancer ( CRC) .Methods The mRNA level of ING1 in 82 matched samples comprising primary CRC and paired non-cancerous mucosa were detected and compared by quantitative RT -PCR.Then the correlations of mRNA level of ING1 with the clinicopathological characteristics and prognosis of patients with CRC were ana -lyzed.Results (1)In the same matched tissues,the expression level of ING1 was significantly higher in normal tissues than that in cancer tissues.(2)mRNA expression of ING1 was associated with certain clinical -pathologic variables such as tumor infiltrating level ,lymphatic metastasis,distant metastasis and advancing TNM stage .(3) We obtained the expression levels ratio of cancer tissue and normal tissue and found the lower ratio has a lower Disease-Free Survival(DFS)(P<0.0001).(4)ING1,as a candidate of tumor suppressor gene ,remained a sta-tistically-significant prognostic marker in the Cox regression analysis .Conclusion Down-regulation of ING1 may be correlated tightly with the occurrence and progression of sporadic colorectal cancer .Its expression level can be used to predict prognosis of CRC .
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Objetcvi e Inhibitor of growth TNG3 is a candidate tumor suppressor gene ,which belongs to the human ING gene family .It has been interested by scientist because of its putative roles as tumor suppressors . There is a low expression level of ING3 in a variety of tumors.However,the relationship of ING3 and the develop-ment of colorectal cancer is unclear yet .The aim of this studyis to examine the expression of ING 3 in colorectal cancer by qRT-PCR.Methods Statistical analysis was performed with the expression of ING 3 mRNA which has been evaluated in 82 matched samples comprising primary colorectal cancer and paired non -cancerous mu-cosa samples.Results In 51%colorectal cancer patients ,the expression level of ING3 was significantly lower in cancer tissue than that in normal tissue .The expression level of ING3 was closely related to pT、pM stage , and TNM stage(P<0.05).The Univariate analysis showed that the pT、pN、pM stage,TNMstage and ING3 expression levels were associated with disease -free survival(P<0.05).CRC patients with low -expression level of ING3 showed shorter disease -free survivals(P<0.05).Conclusion The expression of ING3 might contribute to the CRC development or progression .
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Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are common health problems worldwide. Tumor necrosis factor (TNF) is a type of cytokine that induces inflammation and inhibits tumorigenesis. Several studies have assessed the relationship between the polymorphism of TNF-α-308 G>A and the susceptibility to IBD and CRC; however, the results have been controversial. In addition, the hypothesis whether the increased risk of CRC in IBD patients could be partly ascribed to the polymorphism of TNF-α-308 G>A was unclear. Therefore, we conducted this meta-analysis to confirm these associations. Pooled odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated on the basis of data from 14, 18, and 7 studies from a total of 27 studies for the associations between the polymorphism of TNF-α-308 G>A and ulcerative colitis, Crohn's disease (CD) and CRC. In Europeans, the AA genotype increased the risk of ulcerative colitis (UC) (OR, 2.041; 95% CI, 1.261-3.301) and CD (OR, 1.730; 95% CI, 1.168-2.564) significantly, without obvious heterogeneity and publication bias. Meanwhile, the GA genotype increased the risk of UC in Asians (OR, 2.360; 95% CI, 1.269-4.390) significantly. However, no significant association was observed for CRC in any ethnic population. The results of this meta-analysis suggested that the polymorphism of TNF-α-308 G>A participates in modifying the susceptibility to UC and CD in Europeans and Asians. The increased risk of CRC in IBD patients should be clarified as the combined effects of polymorphisms in TNF-α and other cytokines, and the interaction with environmental factors, in future studies.
