Involvement of Epithelial Cell Transforming Sequence-2 Oncoantigen in Lung and Esophageal Cancer Progression

Hirata, Daizaburo; Yamabuki, Takumi; Miki, Daiki; Ito, Tomoo; Tsuchiya, Eiju; Fujita, Masahiro; Hosokawa, Masao; Chayama, Kazuaki; Nakamura, Yusuke; Daigo, Yataro

doi:10.1158/1078-0432.ccr-08-1672

Cited by 93 publications

(99 citation statements)

References 48 publications

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“…In human lung cancer, multiple studies have revealed involvement of the deregulation of GEFs (18), such as Tiam1, ECT2, and Vav1-3 (19)(20)(21). In agreement, we demonstrated that ARHGEF5 was highly expressed in lung adenocarcinoma tissues and cultured cells.…”

Section: Discussionsupporting

confidence: 86%

Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation

Yang

et al. 2015

Molecular Cancer Therapeutics

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We sought to elucidate the role of Rho guanine nucleotide exchange factor 5 (ARHGEF5) in tumorigenesis of lung adenocarcinoma cells. ARHGEF5 protein levels were assessed in 91 human lung adenocarcinoma specimens, and A549 and NCI-H1650 cells, by IHC and Western blotting. In addition, ARHGEF5 mRNA expression was evaluated by quantitative reverse transcriptase-PCR. Furthermore, ARHGEF5 long and short isoform coexpression was detected by immunofluorescence. Finally, flow cytometry; CCK8 and wound-healing assays; cell invasion, migration and adhesion; and xenografts were used to evaluate the biologic significance of ARHGEF5. ARHGEF5 was significantly increased in lung adenocarcinoma tissues and cell lines. Interestingly, ARHGEF5 levels were significantly associated with tumor grade and pathologic stage, but not age, gender, T stage, or lymph node metastasis status. ARHGEF5 knockdown by RNAi resulted in dramatically reduced proliferation, adhesion, invasion, and migratory capability of A549 and NCI-H1650 cells. Likewise, protein levels of p-Src, p-Akt, and NF-kB were significantly decreased after ARHGEF5 knockdown. In parallel, increased S-phase population and MMP-2/cyclin D1 expression were observed in the cancer cells, which were not apoptotic. In addition, ARHGEF5 knockdown A549 and NCI-H1650 cells injected s.c. and i.v. into nude mice exhibited decreased xenograft volume and overtly reduced metastasis. Conversely, ARH-GEF5 overexpression in A549 and NCI-H1650 cells increased their tumorigenicity in vitro. ARHGEF5 acts as a proto-oncogene in human lung adenocarcinoma cell tumorigenesis.

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Section: Discussionsupporting

confidence: 86%

Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation

Yang

et al. 2015

Molecular Cancer Therapeutics

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“…© 2011 American Association for Cancer clincancerres.aacrjournals.org Downloaded from (27,28). High-level expression of DDX21, a DEAD-box family member, is associated with low survival and rapid relapse of breast cancer (29), and C9orf140, a novel protein with unknown function, show specific expression in primary gastric cancer tissues (30).…”

Section: Discussionmentioning

confidence: 99%

Clinical Validation of Colorectal Cancer Biomarkers Identified from Bioinformatics Analysis of Public Expression Data

Lee¹,

Choi²,

Kim³

et al. 2011

Clinical Cancer Research

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Purpose: Identification of novel biomarkers of cancer is important for improved diagnosis, prognosis, and therapeutic intervention. This study aimed to identify marker genes of colorectal cancer (CRC) by combining bioinformatics analysis of gene expression data and validation experiments using patient samples and to examine the potential connection between validated markers and the established oncogenes such as c-Myc and K-ras.Experimental Design: Publicly available data from GenBank and Oncomine were meta-analyzed leading to 34 candidate marker genes of CRC. Multiple case-matched normal and tumor tissues were examined by RT-PCR for differential expression, and 9 genes were validated as CRC biomarkers. Statistical analyses for correlation with major clinical parameters were carried out, and RNA interference was used to examine connection with major oncogenes.Results: We show with high confidence that 9 (ECT2, ETV4, DDX21, RAN, S100A11, RPS4X, HSPD1, CKS2, and C9orf140) of the 34 candidate genes are expressed at significantly elevated levels in CRC tissues compared to normal tissues. Furthermore, high-level expression of RPS4X was associated with nonmucinous cancer cell type and that of ECT2 with lack of lymphatic invasion while upregulation of CKS2 was correlated with early tumor stage and lack of family history of CRC. We also demonstrate that RPS4X and DDX21 are regulatory targets of c-Myc and ETV4 is downstream to K-ras signaling.Conclusions: We have identified multiple novel biomarkers of CRC. Further analyses of their function and connection to signaling pathways may reveal potential value of these biomarkers in diagnosis, prognosis, and treatment of CRC.

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“…To evaluate the biological functions of Nectin-4 in lung cancer cells, we used small interfering RNA (siRNA) duplexes against the target genes (Dharmacon) as described (37). The target sequences of the synthetic oligonucleotides for RNA interference were as follows: control 1 (a nonspecific control oligo); control 2 (Luciferase:…”

Section: Methodsmentioning

confidence: 99%

Identification of Nectin-4 Oncoprotein as a Diagnostic and Therapeutic Target for Lung Cancer

Takano

Ishikawa²,

Nishino³

et al. 2009

Cancer Research

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175

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Gene expression profile analysis of lung cancers revealed the transactivation of an immunoglobulin-like molecule Nectin-4 in the majority of non-small cell lung cancers (NSCLC). Immunohistochemical staining of 422 NSCLCs showed that a high level of Nectin-4 expression was associated with poor prognosis for NSCLC patients (P < 0.0001), and multivariate analysis confirmed its independent prognostic value (P < 0.0001). We established an ELISA to measure serum Nectin-4 and found that serum Nectin-4 levels were significantly higher in NSCLC patients than in healthy volunteers. The proportion of the serum Nectin-4-positive cases was 88 of 164 (53.7%) NSCLCs, whereas only 3 of 131 (2.3%) healthy volunteers were falsely diagnosed as positive, which was superior to carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA21-1) in sensitivity and specificity. A combined ELISA for both Nectin-4 and CEA increased sensitivity and classified 65.0% of lung adenocarcinomas as positive with false-positive rate of 4.6%. The use of both Nectin-4 and CYFRA21-1 classified 68.3% of lung squamous cell carcinomas as positive with false-positive rate of 6.

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Involvement of Epithelial Cell Transforming Sequence-2 Oncoantigen in Lung and Esophageal Cancer Progression

Cited by 93 publications

References 48 publications

Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation

Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation

Clinical Validation of Colorectal Cancer Biomarkers Identified from Bioinformatics Analysis of Public Expression Data

Identification of Nectin-4 Oncoprotein as a Diagnostic and Therapeutic Target for Lung Cancer

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