Inactivation of &amp;lt;italic&amp;gt;LARS2&amp;lt;/italic&amp;gt;, located at the commonly deleted region 3p21.3, by both epigenetic and genetic mechanisms in nasopharyngeal carcinoma

Kwon

Topics in Current Chemistry

2013

Although aminoacyl-tRNA synthetases (ARSs) and ARS-interacting multi-functional proteins (AIMPs) have long been recognized as housekeeping proteins, evidence indicating that they play a key role in regulating cancer is now accumulating. In this chapter we will review the conventional and non-conventional functions of ARSs and AIMPs with respect to carcinogenesis. First, we will address how ARSs and AIMPs are altered in terms of expression, mutation, splicing, and post-translational modifications. Second, the molecular mechanisms for ARSs' and AIMPs' involvement in the initiation, maintenance, and progress of carcinogenesis will be covered. Finally, we will introduce the development of therapeutic approaches that target ARSs and AIMPs with the goal of treating cancer.

Section: Large Scale Mutationsmentioning

confidence: 99%

Association of Aminoacyl-tRNA Synthetases with Cancer

Kwon

Topics in Current Chemistry

2013

“…The only malignant disease with known connection to this gene is nasopharyngeal carcinoma; however, in this case, it is associated with decreased expression due to frequent deletion of locus 3p21.3, and even the authors of this study found no other source of evidence of its role in tumorigenesis in the literature 27 . Based on our data, it seems that there are different clones of PC in the BM of EM patients when compared to the tumors.…”

Section: Discussionmentioning

confidence: 51%

Extramedullary relapse of multiple myeloma defined as the highest risk group based on deregulated gene expression data

Ševčı́ková¹,

Paszekova

Bešše³

et al. 2015

BIOMED PAP

Background. Multiple myeloma (MM) is characterized by malignant proliferation of plasma cells (PC) which accumulate in the bone marrow (BM). The advent of new drugs has changed the course of the disease from incurable to treatable, but most patients eventually relapse. One group of MM patients (10-15%) is considered high-risk because they relapse within 24 months. Recently, extramedullary relapse of MM (EM) has been observed more frequently. Due to its aggressivity and shorter survival, EM is also considered high-risk. Aims. The goal of this study was to determine if the so-called high-risk genes published by the University of Arkansas group (UAMS) are even more deregulated in EM patients than in high-risk MM patients and if these patients may be considered high-risk. Methods. Nine samples of bone marrow plasma cells from MM patients as well as 9 tumors and 9 bone marrow plasma cells from EM patients were used. Quantitative real-time PCR was used for evaluation of expression of 15 genes connected to the high-risk signature of MM patients. Results. Comparison of high-risk plasma cells vs extramedullary plasma cells revealed 4 significantly deregulated genes (CKS1B, CTBS, NADK, YWHAZ); moreover, comparison of extramedullary plasma cells vs extramedullary tumors revealed significant differences in 9 out of 15 genes. Of these, 6 showed significant changes as described by the UAMS group (ASPM, SLC19A1, NADK, TBRG4, TMPO and LARS2). Conclusions. Our data suggest that increasing genetic abnormalities as described by the gene expression data are associated with increased risk for EM relapse.

“…CDC42 levels in tumor samples did not correlate with prognosis, however we found that three genes have an improved prognostic value when combined with CDC42 status: LARS2, REG1CP and CACNA2D2 . Inactivation of LARS2 (leucyl-tRNA synthetase in mitochondria) has been described in nasopharyngeal cancer cells [33], and dysregulation of aminoacyl-tRNA synthesis has also been widely linked to tumorigenesis [34], however this is the first report showing a transcriptional link between CDC42 and LARS2 in CRC. REG1CP (Regenerating Family Member 1 Gamma) is a pseudogene and is affiliated with the long non-coding RNA class, its physiological function is still unknown, so to our knowledge this is the first report to show its transcriptional association with CDC42 and its significant correlation with prognosis in CRC.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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.