Abstract
PurposeRecent studies indicated undisputed contribution of connective tissue growth factor (CTGF) in the development of many cancers, including non-small cell lung cancer (NSCLC). However, the functional role and regulation of CTGF expression during tumorigenesis remain elusive. Our goal was to determine CTGF transcript and protein levels in tumoral and matched control tissues from 98 NSCLC patients, to correlate the results with clinicopathological features and to investigate whether the CTGF expression can be epigenetically regulated in NSCLC.MethodsWe used quantitative PCR, Western blotting and immunohistochemistry to evaluate CTGF expression in lung cancerous and histopathologically unchanged tissues. We tested the impact of 5-Aza-2′-deoxycytidine (5-dAzaC) and trichostatin A (TSA) on CTGF transcript and protein levels in NSCLC cells (A549, Calu-1). DNA methylation status of the CTGF regulatory region was evaluated by bisulfite sequencing. The influence of 5-dAzaC and TSA on NSCLC cells viability and proliferation was monitored by the trypan blue assay.ResultsWe found significantly decreased levels of CTGF mRNA and protein (both p < 0.0000001) in cancerous tissues of NSCLC patients. Down-regulation of CTGF occurred regardless of gender in all histological subtypes of NSCLC. Moreover, we showed that 5-dAzaC and TSA were able to restore CTGF mRNA and protein contents in NSCLC cells. However, no methylation within CTGF regulatory region was detected. Both compounds significantly reduced NSCLC cells proliferation.ConclusionsDecreased expression of CTGF is a common feature in NSCLC; however, it can be restored by the chromatin-modifying agents such as 5-dAzaC or TSA and consequently restrain cancer development.Electronic supplementary materialThe online version of this article (doi:10.1007/s00432-016-2195-3) contains supplementary material, which is available to authorized users.
Highlights
Lung cancer (LC) is the most common cancer in the world, with more than 1 million cases reported annually (Jemal et al 2011)
Decreased expression of Connective tissue growth factor (CTGF) is a common feature in non-small cell lung cancer (NSCLC); it can be restored by the chromatin-modifying agents such as 5-dAzaC or trichostatin A (TSA) and restrain cancer development
In the present study, employing RT-qPCR and Western blotting, we found significantly lowered levels of CTGF transcript (p < 0.0000001) and protein (p < 0.0000001) in lung cancerous tissues compared with adjacent histopathologically unchanged tissues obtained from 98 patients with NSCLC (Fig. 1a–c)
Summary
Lung cancer (LC) is the most common cancer in the world, with more than 1 million cases reported annually (Jemal et al 2011). Lung carcinogenesis is one of the most extensively studied disorders, it is a very complex process that still requires clarification In these days, a lot of studies focus on the interplay between tumor cells and surrounding stromal cells with an extracellular matrix (ECM) that both create the tumor microenvironment (Mbeunkui and Johann 2009; Lu et al 2012; Sainio and Järveläinen 2014). ECM is a complex network of macromolecules and secretory proteins that regulate cell–cell and cell–matrix interactions, cellular behavior, as well as tissue polarity and architecture. This network is commonly deregulated during malignant transformation and plays a crucial role in the tumor development and progression (Lu et al 2012)
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