Clinical relevance of the transcriptional signature regulated by CDC42 in colorectal cancer

Abstract

CDC42 is an oncogenic Rho GTPase overexpressed in colorectal cancer (CRC). Although CDC42 has been shown to regulate gene transcription, the specific molecular mechanisms regulating the oncogenic ability of CDC42 remain unknown. Here, we have characterized the transcriptional networks governed by CDC42 in the CRC SW620 cell line using gene expression analysis. Our results establish that several cancer-related signaling pathways, including cell migration and cell proliferation, are regulated by CDC42. This transcriptional signature was validated in two large cohorts of CRC patients and its clinical relevance was also studied. We demonstrate that three CDC42-regulated genes offered a better prognostic value when combined with CDC42 compared to CDC42 alone. In particular, the concordant overexpression of CDC42 and silencing of the putative tumor suppressor gene CACNA2D2 dramatically improved the prognostic value. The CACNA2D2/CDC42 prognostic classifier was further validated in a third CRC cohort as well as in vitro and in vivo CRC models. Altogether, we show that CDC42 has an active oncogenic role in CRC via the transcriptional regulation of multiple cancer-related pathways and that CDC42-mediated silencing of CACNA2D2 is clinically relevant. Our results further support the use of CDC42 specific inhibitors for the treatment of the most aggressive types of CRC.

Molecular Characterization and Prognosis of Lactate-Related Genes in Lung Adenocarcinoma

“…In this study, the prognosis model was established according to the expression of CACNA2D2, CYP2B7P, and KRT6A, which was accurate in predicting the OS in LUAD. Studies have shown that CACNA2D2 plays an important role in several cancers, including endometrial cancer [ 37 ], colorectal cancer [ 38 ], and NSCLC [ 39 ]. CACNA2D2 overexpression inhibited cell proliferation in NSCLC.…”

An integrated analysis of mRNA-miRNA transcriptome data revealed hub regulatory networks in three genitourinary cancers

“…The small GTPase RHEB promotes cancer cell survival throughp27Kip1dependent activation of autophagy (Campos et al, 2016), and it also functions in liver cancer, colon cancer cells, bladder cancer and prostate cancer (Kobayashi et al, 2010;Campos et al, 2013;Tigli et al, 2013;Zheng et al, 2015). CDC42 (cell division control 42 homolog) has multiple functions in breast cancer, metastatic cancer, non-small cell lung cancer and colorectal cancer (Chrysanthou et al, 2017;Humphries-Bickley et al, 2017;Li et al, 2017b;Valdes-Mora et al, 2017). TTN (Topotecan) functions in ovarian cancer (Buckley et al, 2005).…”

Evolutionary Analysis of TCGA Data Using Over- and Under- Mutated Genes Identify Key Molecular Pathways and Cellular Functions in Lung Cancer Subtypes

“…By this metric, no conserved genes were common to all three subtypes and only 14 were found in more than one subtype including REV3L in EGFR-mut and KRAS-mut; HTT and VPS13D in EGFR-mut and NEK; MDN1, SPATA31A7, NBPF10, LRRC37A2, NPIPB5, NBPF11, SPATA31C2, ZNF729, RGPD6, RIMBP3, and CACNA2D2 in KRAS-mut and NEK. Interestingly, most of these conserved genes have not been extensively investigated in LUAD, although some have been identified in broad molecular cancer risk and prognosis studies [27][28][29]. Nevertheless, our conservation and expression data suggest these genes have been activated and are useful and perhaps essential for their normal, unaltered function.…”