Novel insights into Notum and glypicans regulation in colorectal cancer

Robertis, Mariangela De; Arigoni, Maddalena; Loiacono, Luisa; Riccardo, Federica; Calogero, Raffaele; Feodorova, Yana; Tashkova, D.; Belovejdov, V.; Sarafian, Victoria; Cavallo, Federica; Signori, Emanuela

doi:10.18632/oncotarget.5652

Cited by 56 publications

(38 citation statements)

References 63 publications

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“…Therefore, additional predictive factors of prognosis are needed to better evaluate therapy outcomes and help develop individualized treatment plans. Several methods have been used to identify new biomarkers for CRC, including translational approaches investigating perturbations in gene expression or genomic instability, which can be identified using animal models of CRC [21], and high-throughput technologies such as massive parallel sequencing [22]. Bioinformatics methods combined with public cancer databases also have been widely used to find potential biomarkers.…”

Section: Discussionmentioning

confidence: 99%

TACC3 promotes colorectal cancer tumourigenesis and correlates with poor prognosis

Liu

Wang

et al. 2016

Oncotarget

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Colorectal carcinoma (CRC) is a malignant epithelial tumour with tremendous invasion and metastatic capacity. Transforming acidic coiled-coil protein-3 (TACC3), a frequently aberrantly expressed oncogene, is an important biomarker in various human cancers. Our study aimed to investigate the expression and function of TACC3 in human CRC. We found that TACC3 was over-expressed at both the mRNA and protein levels in CRC cells and in biopsies of CRC tissues compared with normal controls as determined by qRT-PCR, western blot and immunohistochemical (IHC) staining assays. IHC staining of samples from 161 patients with CRC also revealed that TACC3 expression was significantly correlated with clinical stage (P = 0.045), T classification (P = 0.029) and M classification (P = 0.020). Multivariate analysis indicated that high TACC3 expression was an independent prognostic marker for CRC. Patients who had high TACC3 expression had significantly poorer overall survival (OS, P = 0.023) and disease-free survival (DFS, P = 0.019) compared to patients who had low TACC3 expression. Furthermore, TACC3 knockdown attenuated CRC cell proliferation, colony formation capability, migration and invasion capability, and tumourigenesis in nude mice; these properties were measured using a real-time cell analyser (RTCA), clonogenicity analysis, and transwell and xenograft assays, respectively. These data indicate that TACC3 promotes CRC progression and could be an independent prognostic factor and a potential therapeutic target for CRC.

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Section: Discussionmentioning

confidence: 99%

TACC3 promotes colorectal cancer tumourigenesis and correlates with poor prognosis

Liu

Wang

et al. 2016

Oncotarget

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“…The AOM/DSS model employed in this study (also called as “two step model”, i.e. one injection of AOM and three cycles of DSS) is a chronic inflammation-related model in which the initial inflammatory microenvironment is essential to promote and accelerate the malignant progression which starts after the AOM administration [42]. The damage of inflammatory microenvironment can activate the TLRs signal.…”

Section: Discussionmentioning

confidence: 99%

“…Mice were administered with a single intraperitoneal injection of the AOM (Sigma-Aldrich, 10 mg/kg body weight) and subsequently three rounds of 2.5% DSS (Sigma-Aldrich) orally (7 days each round and 14 days interval between the 2 rounds) [42]. For treatment, 7 days after injection of the AOM, mice were administered with sTLR4, MD-2, sTLR4/MD-2, PBS by i.p., and then repeated every 5 days until the last week (Figure 5G, upper).…”

Section: Methodsmentioning

confidence: 99%

sTLR4/MD-2 complex inhibits colorectal cancer in vitro and in vivo by targeting LPS

et al. 2016

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Colorectal cancer (CRC) is aggressive and associated with TLR4-MD-2 signaling. Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2) were highly expressed in human CRC. The soluble form of extracellular TLR4 domain (sTLR4) and MD-2 may have important roles in binding lipopolysaccharide (LPS). In this study, sTLR4 and MD-2 protein and prepared sTLR4/MD-2 complex were synthesized successfully to restrain LPS-TLR4/MD-2 activation by competing with cellular membrane TLR4 for binding LPS. The sTLR4/MD-2 complex can significantly attenuate LPS induced pro-inflammatory and migration cytokine production in vitro and in vivo, and inhibit the effect of LPS on the cell cycle, migration and invasion of human CRC cells in vitro. Administration of sTLR4/MD-2 complex protected mice from tumor both in xenograft and implantation metastasis model. The sTLR4/MD-2 complex treated mice had smaller tumor, less body weight loss and lower expression of inflammatory cytokines. Here, the azoxymethane/dextran sulfate sodium salt (AOM/DSS) murine model was used as an experimental platform to simulate the physiological and pathological processes of cancers associated with chronic intestinal inflammation. AOM/DSS-induced tumors were inhibited in mice treated by sTLR4/MD-2 complex. It is demonstrated in our study that sTLR4/MD-2 complex could inhibit CRC by competing with binding LPS, raising the complex's possibility of a new prevention agent against CRC.

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“…We made use of the chemically-induced AOM/DSS murine model of sporadic colon carcinogenesis taking advantage of its high reproducibility and ability to recapitulate, within a predictable time line, colorectal lesions distinctive of human CRC development (18,19). …”

Section: Introductionmentioning

confidence: 99%

Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer

Robertis

Loiacono

Fusilli

et al. 2017

Clinical Cancer Research

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Purpose EphA2 receptor is involved in multiple cross-talks with other cellular networks including EGFR, FAK and VEGF pathways, with which it collaborates to stimulate cell migration, invasion and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular crosstalk and microRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in CRC patients. Experimental Design Gene expression analysis was performed in EphA2high cells isolated from CRC of AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response. Results We identified a gene expression pattern (EphA2, Efna1, EGFR, Ptpn12, Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such pattern showed prognostic significance in stage I-III CRC patients, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/EGFR gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status. Conclusions These results suggest that EphA2/Efna1/EGFR genes, linked to a possible control by mir-200a and mir-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations.

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Novel insights into Notum and glypicans regulation in colorectal cancer

Cited by 56 publications

References 63 publications

TACC3 promotes colorectal cancer tumourigenesis and correlates with poor prognosis

TACC3 promotes colorectal cancer tumourigenesis and correlates with poor prognosis

sTLR4/MD-2 complex inhibits colorectal cancer in vitro and in vivo by targeting LPS

Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer

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