[Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer]
Abstract:
Chromosomal and genome abnormalities of 3p are frequent events in many epithelial tumours, including lung cancer. Several critical regions with high frequency of hemi--and homozygous deletions in tumours were detected on 3p and more then 20 different cancer-related genes were identified in 3p21.3 locus. Real-time PCR was used to measure mRNA level of tumour-suppressor genes and candidates in 3p21.3 (RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 in basic types of non-small cell lung cancer (NSCLC)--squamous cell lung cancer (SCC) and lung adenocarcinoma (AC). Significant (from 2 to 100 times) and frequent (from 44 to 100%) mRNA level decrease was shown in NSCLC. Level and frequency of mRNA decrease for all genes depended on histological type of NSCLC. Down-regulation of RASSF1A and ITGA9 was associated significantly with AC progression, the same tendency was found for genes RBSP3/CTDSPL, NPRL2/G21, HYAL1 and HYAL2. On the contrary, down-regulation of all genes in SCC was not associated with clinical stages, tumor cells differentiation and metastases in lymph nodes. Significant decrease of RBSP3/CTDSPL, NPRL2/G21, ITGA9, HYAL1 and HYAL2 mRNA levels (on average, 5-13 times) with high frequency (83-100%) was already shown at the first stage of SCC. Simultaneous decrease of all six genes mRNA level was found in the same tumor samples and was not depended on their localization on 3p21.3 and functions of the proteins. Spearman's correlation coefficient r(s) was from 0.63 to 0.91, P < 0.001. Co-regulation of gene pairs ITGA9 and HYAL2, HYAL1 and HYAL2, which mediate cell-cell adhesion and cell-matrix interaction, was suggested based on the obtained data. It was shown that genetic and epigenetic mechanisms were important for down-regulation of RBSP3/CTDSPL and ITGA9 genes. These results supported the hypothesis on simultaneous inactivation of cluster cancer-related genes in extended 3p21.3 locus during development and progression of lung cancer and other epithelial tumors. Significant and frequent decrease of mRNA level of six genes in SCC could be important for development of specific biomarker sets for early SCC diagnosis and new therapeutic approaches/strategies for NSCLC.
Insights
Chromosomal abnormalities in 3p are common in lung cancer. This study found frequent mRNA level decreases in six tumor-suppressor genes in non-small cell lung cancer (NSCLC), suggesting potential biomarkers for early diagnosis.
Area of Science:
- Genetics and Oncology
- Molecular Biology
Context:
- Chromosomal abnormalities, specifically on chromosome 3p, are frequently observed in epithelial tumors, including lung cancer.
- The 3p21.3 locus is known to harbor numerous cancer-related genes, with deletions often implicated in tumor development.
Purpose:
- To investigate the mRNA expression levels of six candidate tumor-suppressor genes (RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1, and HYAL2) located in the 3p21.3 region.
- To analyze these expression levels in different histological subtypes of non-small cell lung cancer (NSCLC): squamous cell lung cancer (SCC) and lung adenocarcinoma (AC).
- To correlate gene expression changes with clinicopathological features such as tumor stage, differentiation, and metastasis.
Summary:
- A significant and frequent decrease in mRNA levels (2-100 fold) was observed for all six genes in NSCLC, with variations between SCC and AC.
- In AC, down-regulation of RASSF1A and ITGA9, and a similar trend for RBSP3/CTDSPL, NPRL2/G21, HYAL1, and HYAL2, correlated with tumor progression.
- In SCC, significant mRNA down-regulation of RBSP3/CTDSPL, NPRL2/G21, ITGA9, HYAL1, and HYAL2 was observed early (stage I) and frequently (83-100%), without association with clinical stages or metastasis. Simultaneous down-regulation of all six genes was noted, suggesting co-regulation and potential coordinated inactivation. Genetic and epigenetic mechanisms were implicated in the down-regulation of RBSP3/CTDSPL and ITGA9.
Impact:
- The findings support the hypothesis of simultaneous inactivation of clustered cancer-related genes in the 3p21.3 locus during lung cancer development and progression.
- The frequent and significant down-regulation of these six genes in early-stage SCC suggests their potential utility as biomarkers for early diagnosis.
- These results may pave the way for developing novel therapeutic strategies targeting NSCLC.
Related Concept Videos
Negative Regulator Molecules
The Ras Gene
Ras is a superfamily...
Abnormal Proliferation
Small GTPases - Ras and Rho
Three regulatory proteins control their activity:
The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
