SCG3 Transcript in Peripheral Blood Is a Prognostic Biomarker for REST-Deficient Small Cell Lung Cancer

Abstract

Purpose: Specific markers of circulating tumor cells may be informative in managing lung cancer.Because the RE-1silencing transcription factor (REST/NRSF) is a transcriptional repressor that is inactivated in neuroendocrine lung cancer, we identified REST-regulated transcripts (CHGA, CHGB, SCG3,VGF, and PCSK1) for evaluation as biomarkers in peripheral blood. Experimental Design: Transcripts were screened across lung cancer and normal cell lines. Candidates were assessed by reverse transcription-PCR and hybridization of RNA extracted from the peripheral blood of 111 lung cancer patients obtained at clinical presentation and from 27 cancer-free individuals. Results: Expression profiling revealed multiple chromogranin transcripts were readily induced on RESTdepletion, most notably SCG3 was induced >500-fold.The SCG3 transcript was also overexpressed by 12,000-fold in neuroendocrine compared with nonneuroendocrine lung cancer cells. In peripheral blood of lung cancer patients and cancer-free individuals, we found that SCG3 was more tumor-specific and more sensitive than other chromogranin transcripts as a biomarker of circulating tumor cells. Overall, 36% of small cell lung cancer (SCLC) and 16% of non-SCLC patients scored positively for normalized SCG3 transcript. This correlated with worse survival among SCLC patients with limited disease (n = 33; P = 0.022) but not extensive disease (n = 29; P = 0.459). Interestingly, the subcohort of 6 SCLC patients with resistance to platinum/ etoposide chemotherapy all scored positively for peripheral blood SCG3 transcript (P = 0.022). Conclusions: SCG3 mRNA, a component of the REST-dependent neurosecretory transcriptional profile, provides a sensitive prognostic biomarker for noninvasive monitoring of neuroendocrine lung cancer.

Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer

“…Here, we show that cell differentiation and growth in SCLC mediated by NRSF/REST are subject to upstream regulation by methylation, which modulates downstream AKT2 signalling. The expression of neuronal genes is a phenotypic hallmark of SCLC tissue and cell lines (Coulson et al, 2000;Gurrola-Diaz et al, 2003;Neumann et al, 2004;Onganer et al, 2005;Moss et al, 2009). In this study, we determined transcripts of various neuronal marker genes in SCLC lines and correlated expression levels with those of NRSF/REST and its splice variant sNRSF, thus extending other reports on SCLC lines with reduced NRSF/REST expression.…”

“…In two SCLC lines, a complete loss of NRSF/REST transcription resulted in an increased expression of the neuronal markers, neural cell adhesion molecule (NCAM), L1-cell adhesion molecule (L1-CAM) and voltage-gated calcium channels (Neumann et al, 2004). A recent study identified the SCG3 transcript as a prognostic biomarker for NRSF/REST-deficient SCLC (Moss et al, 2009). Here, we show that NRSF/ REST-mediated cell differentiation and growth in SCLC is subject to upstream regulation by methylation, which ultimately affected the downstream AKT2 pathway.…”

EWS and RE1-Silencing Transcription Factor Inhibit Neuronal Phenotype Development and Oncogenic Transformation in Ewing Sarcoma

“…Interestingly, elevated CHGA is an indicator for pancreas and prostate cancers. 36 Detection of SCG3 and VGF transcripts is a prognostic biomarker for small cell lung cancer and large cell neuroendocrine carcinoma, 37,38 respectively. More importantly, a putative REST response element (neuron-restrictive silencer element [NRSE]) is found in the regulatory regions such as the promoter or 5′ untranslated region (5′-UTR) of each of these genes (Suppl.…”

L1CAM malfunction in the nervous system and human carcinomas

“…It appears conceivable that dysregulation of REST/NRSF may also play a role in aberrant L1 expression in human carcinomas. For example, REST/ NRSF has been found to be inactivated in small-cell lung cancer [106], and increased expression levels of the neuronal isoform of L1 have been found in cells of the smallcell lung carcinoma cell line NCI-H69 [107].…”