Biology and therapeutic implications of VEGF-A splice isoforms and single-nucleotide polymorphisms in colorectal cancer

Canavese, Miriam; Ngo, D.; Maddern, Guy J.; Hardingham, Jennifer E.; Price, Timothy; Hauben, Ehud

doi:10.1002/ijc.30567

Cited by 35 publications

(34 citation statements)

References 74 publications

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“…This is a CNV region that encompasses the chromatin modifier CHD8, which has been significantly associated with sporadic CRC risk [26]. Regarding the NP group, in 6p21 (one of the most frequently gained regions), VEGFA is located, which encodes a growth factor from the PDGF/VEGF family, responsible for the induction of vascular endothelial cell migration and proliferation, thus playing a pivotal role in angiogenesis, both in physiological and pathological conditions [27]. In one of the most frequently lost regions, in 9p11, microRNA-1299 is encoded, a negative CRC regulator of STAT3 that is essential for cancer progression to advanced malignancy [28].…”

Section: Discussionmentioning

confidence: 99%

Association of Polyps with Early-Onset Colorectal Cancer and Throughout Surveillance: Novel Clinical and Molecular Implications

García

Arribas

Cañete

et al. 2019

Cancers

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Early-onset colorectal cancer (EOCRC) is an increasing and worrisome entity. The aim of this study was to analyze its association with polyps concerning prognosis and surveillance. EOCRC cases were compared regarding the presence or absence of associated polyps (clinical and molecular features), during a minimum of 7 years of follow-up. Of 119 cases, 56 (47%) did not develop polyps (NP group), while 63 (53%) did (P group). The NP group showed a predominant location of the CRC in the rectum (50%), of sporadic cases (54%), and diagnosis at advanced stages: Only P53 and SMARCB1 mutations were statistically linked to this group. The P group, including mainly early-diagnosed tumors, was linked with the most frequent and differential altered chromosomal regions in the array comparative genomic hybridization. The two most frequent groups according to the follow-up were the NP group (40%), and patients developing polyps in the first 5 years of follow-up (P < 5FU) (34%) (these last groups predominantly diagnosed at the earliest stage and with adenomatous polyps (45%)). EOCRC with polyps that developed during the entire follow-up (PDFU group) were mainly located in the right colon (53%), diagnosed in earlier stages, and 75% had a familial history of CRC. Patients developing polyps after the first 5 years (P > 5FU) showed a mucinous component (50%). Our results show that the absence or presence of polyps in EOCRC is an important prognostic factor with differential phenotypes. The development of polyps during surveillance shows that it is necessary to extend the follow-up time, also in those cases with microsatellite-stable EOCRC.

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Section: Discussionmentioning

confidence: 99%

Association of Polyps with Early-Onset Colorectal Cancer and Throughout Surveillance: Novel Clinical and Molecular Implications

García

Arribas

Cañete

et al. 2019

Cancers

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“…Therefore, in the present study, the associations among EDA + FN, vessels, and bone destruction in radicular cysts were investigated. Bevacizumab [15] or the type II bacterial clustered, regularly interspaced, palindromic repeats (CRISPR)-associated (Cas) system [2,4] was used to block the effects of either VEGF or EDA + FN [16], respectively, and inhibit osteoclastogenesis.…”

Section: Introductionmentioning

confidence: 99%

Bevacizumab or fibronectin gene editing inhibits the osteoclastogenic effects of fibroblasts derived from human radicular cysts

Wang

Chen

et al. 2018

Acta Pharmacol Sin

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Fibronectin (FN) is a main component of extracellular matrix (ECM) in most adult tissues. Under pathological conditions, particularly inflammation, wound healing and tumors, an alternatively spliced exon extra domain A (EDA) is included in the FN protein (EDA + FN), which facilitates cellular proliferation, motility, and aggressiveness in different lesions. In this study we investigated the effects of EDA + FN on bone destruction in human radicular cysts and explored the possibility of editing FN gene or blocking the related paracrine signaling pathway to inhibit the osteoclastogenesis. The specimens of radicular cysts were obtained from 20 patients. We showed that the vessel density was positively associated with both the lesion size (R = 0.49, P = 0.001) and EDA + FN staining (R = 0.26, P = 0.022) in the specimens. We isolated fibroblasts from surgical specimens, and used the CRISPR/Cas system to knockout the EDA exon, or used IST-9 antibody and bevacizumab to block EDA + FN and VEGF, respectively. Compared to control fibroblasts, the fibroblasts from radicular cysts exhibited significantly more Trap + MNCs, the relative expression level of VEGF was positively associated with both the ratio of EDA + FN/total FN (R = 0.271, P = 0.019) and with the number of Trap + MNCs (R = 0.331, P = 0.008). The knockout of the EDA exon significantly decreased VEGF expression in the fibroblasts derived from radicular cysts, leading to significantly decreased osteoclastogenesis; similar results were observed using bevacizumab to block VEGF, but block of EDA + FN with IST-9 antibody had no effect. Furthermore, the inhibitory effects of gene editing on Trap + MNC development were restored by exogenous VEGF. These results suggest that EDA + FN facilitates osteoclastogenesis in the fibrous capsule of radicular cysts, through a mechanism mediated by VEGF via an autocrine effect on the fibroblasts. Bevacizumab inhibits osteoclastogenesis in radicular cysts as effectively as the exclusion of the EDA exon by gene editing.

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“…[ 6 ] SNPs are often performed as genetic markers for the prediction of patient response to susceptibility and development of CRC. [ 7 ] A recent polymorphism study showed that the RAD52 rs1051669 AA genotype was associated with a significantly increased risk of developing CRC. [ 8 ] Interestingly, in another genetic study, the functional RAD52 rs7963551 polymorphism contributed to risk susceptibility of hepatitis B virus related hepatocellular carcinoma in Chinese populations.…”

Section: Introductionmentioning

confidence: 99%

RAD52 gene polymorphisms are associated with risk of colorectal cancer in a Chinese Han population

Zhang

Tang

et al. 2017

Medicine

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Upward trends in the incidence and mortality rates of colorectal cancer (CRC) in China over the past decade mean that it is critical to improve survival outcomes for patients with this malignancy. Analysis of genetic variants may identify biomarkers that have a role in CRC susceptibility and clinical outcomes in Chinese patients with CRC. RAD52 is a key mediator during DNA strand exchange and homologous recombination within mammalian cells. In this study, we explored the effects of RAD52 single nucleotide polymorphisms (SNPs) in the susceptibility and clinicopathological characteristics of Chinese Han patients with CRC. Five RAD52 SNPs (rs1051669, rs10774474, rs11571378, rs6489769, and rs7963551) were analyzed using TaqMan SNP genotyping in 281 patients with CRC and 309 healthy controls. Among those aged over 60 years in the total population, carriers of the variant C allele or at least one T allele of the rs1051669 SNP were at a lower risk of CRC than carriers of the wild-type CC variant of rs1051669, while in those carrying the rs7963551 SNP, the GT or GT+GG alleles were associated with an increased risk of CRC compared with patients carrying TT alleles. We indicated a significant correlation between RAD52 rs7963551 polymorphism and lymph node metastasis in CRC patients. In all patients, the T-T-T-T-T, C-T-T-T-T, and C-T-A-C-T haplotypes were associated with an increasing risk of CRC. Our findings suggest that 4 RAD52 SNPs (rs1051669, rs10774474, rs11571378, and rs6489769) might contribute to the prediction of CRC susceptibility. In conclusion, our study demonstrated that RAD52 polymorphisms were associated with CRC in a Chinese Han cohort.

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Biology and therapeutic implications of VEGF-A splice isoforms and single-nucleotide polymorphisms in colorectal cancer

Cited by 35 publications

References 74 publications

Association of Polyps with Early-Onset Colorectal Cancer and Throughout Surveillance: Novel Clinical and Molecular Implications

Association of Polyps with Early-Onset Colorectal Cancer and Throughout Surveillance: Novel Clinical and Molecular Implications

Bevacizumab or fibronectin gene editing inhibits the osteoclastogenic effects of fibroblasts derived from human radicular cysts

RAD52 gene polymorphisms are associated with risk of colorectal cancer in a Chinese Han population

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