Alterations in Gene Expression of Proprotein Convertases in Human Lung Cancer Have a Limited Number of Scenarios

Abstract

Proprotein convertases (PCs) is a protein family which includes nine highly specific subtilisin-like serine endopeptidases in mammals. The system of PCs is involved in carcinogenesis and levels of PC mRNAs alter in cancer, which suggests expression status of PCs as a possible marker for cancer typing and prognosis. The goal of this work was to assess the information value of expression profiling of PC genes. Quantitative polymerase chain reaction was used for the first time to analyze mRNA levels of all PC genes as well as matrix metalloproteinase genes MMP2 and MMP14, which are substrates of PCs, in 30 matched pairs of samples of human lung cancer tumor and adjacent tissues without pathology. Significant changes in the expression of PCs have been revealed in tumor tissues: increased FURIN mRNA level (p<0.00005) and decreased mRNA levels of PCSK2 (p<0.007), PCSK5 (p<0.0002), PCSK7 (p<0.002), PCSK9 (p<0.00008), and MBTPS1 (p<0.00004) as well as a tendency to increase in the level of PCSK1 mRNA. Four distinct groups of samples have been identified by cluster analysis of the expression patterns of PC genes in tumor vs. normal tissue. Three of these groups covering 80% of samples feature a strong elevation in the expression of a single gene in cancer: FURIN, PCSK1, or PCSK6. Thus, the changes in the expression of PC genes have a limited number of scenarios, which may reflect different pathways of tumor development and cryptic features of tumors. This finding allows to consider the mRNAs of PC genes as potentially important tumor markers.

The proprotein convertase furin in tumour progression

“…observed a selective and strong furin mRNA expression in lung cancer tissues derived from non‐small cell lung cancer (NSCLC), but not in those derived from small cell lung cancer (SCLC) . Other studies detected high furin mRNA levels in lung squamous cell carcinomas and adenocarcinomas of the lungs . Moreover, furin mRNA and protein levels appeared to correlate with the invasive potential of NSCLC cell lines and furin protein expression was found in the majority of invasive squamous cell carcinomas (SCC) of the lung .…”

“…Functional studies showed that inhibition of furin activity, either through genetic silencing or through application of the inhibitors PDX or CMK, decreases processing of the insulin‐like growth factor 1 receptor (IGF1R), cell proliferation, in vitro migration and invasion abilities, as well as in vivo tumour growth . These observations indicate that furin expression is not only a potential marker, but also a potential therapeutic target for lung carcinomas.…”

“…24 Other studies detected high furin mRNA levels in lung squamous cell carcinomas and adenocarcinomas of the lungs. [25][26][27] Moreover, furin mRNA and protein levels appeared to correlate with the invasive potential of NSCLC cell lines 28 and furin protein expression was found in the majority of invasive squamous cell carcinomas (SCC) of the lung. 29 Elevated levels of furin in NSCLC cell lines likely relies on the activity of PTGS2 and the transcription factor E2F1, as interference with either one decreases furin activity.…”

Targeting proprotein convertases in furin‐rich lung cancer cells results in decreased in vitro and in vivo growth

“…Thus, furin is an attractive candidate as a therapeutic target in human cancer because it is overexpressed in human cancer cell lines and primary squamous cell carcinomas from lung, head, and neck among many others . In addition, previous reports on PCs and cancer describe the increase expression of PCs in primary lung cancers and the possible use of furin as a tumor marker, that is, furin is overexpressed in non‐small cell lung carcinoma and not in small cell carcinomas and has been proposed as a marker to differentiate between these two tumor types . Given furin's role in processing cancer relevant substrates, its inhibition could open a new therapeutic alternative, either used alone or in combination with other drugs in the treatment of lung cancer.…”

Clinical Advances in Molecular Biomarkers for Cancer Diagnosis and Therapy

“…At the RNA level, the changes are seen in transcription and post-transcriptional modifications [4,13], and at the protein level, it is seen at the translation and post-translational effects [23,24] as depicted in Figure 1.…”