HOPX
Homeodomain-only protein (Lung cancer-associated Y protein) (Not expressed in choriocarcinoma protein 1) (Odd homeobox protein 1) [HOD] [HOP] [LAGY] [NECC1] [OB1]
Publications[править]
Distal lung epithelium is maintained by proliferation of alveolar type II (AT2) cells and, for some daughter AT2 cells, transdifferentiation into alveolar type I (AT1) cells. We investigated if subpopulations of alveolar epithelial cells (AEC) exist that represent various stages in transdifferentiation from AT2 to AT1 cell phenotypes in normal adult lung and if they can be identified using combinations of cell-specific markers. Immunofluorescence microscopy showed that, in distal rat and mouse lungs, ∼ 20-30% of NKX2.1( ) (or thyroid transcription factor 1( )) cells did not colocalize with pro-surfactant protein C (pro-SP-C), a highly specific AT2 cell marker. In distal rat lung, NKX2.1( ) cells coexpressed either pro-SP-C or the AT1 cell marker homeodomain only protein x (HOPX). Not all HOPX( ) cells colocalize with the AT1 cell marker aquaporin 5 (AQP5), and some AQP5( ) cells were NKX2.1( ). HOPX was expressed earlier than AQP5 during transdifferentiation in rat AEC primary culture, with robust expression of both by day 7. We speculate that NKX2.1 and pro-SP-C colocalize in AT2 cells, NKX2.1 and HOPX or AQP5 colocalize in intermediate or transitional cells, and HOPX and AQP5 are expressed without NKX2.1 in AT1 cells. These findings suggest marked heterogeneity among cells previously identified as exclusively AT1 or AT2 cells, implying the presence of subpopulations of intermediate or transitional AEC in normal adult lung.
MeSH Terms
- Aging
- Alveolar Epithelial Cells
- Animals
- Antigens, Differentiation
- Cell Differentiation
- Cell Transdifferentiation
- Cells, Cultured
- Epithelial Cells
- Mice
- Pulmonary Alveoli
- Rats
Keywords
- NKX2.1
- alveolar epithelial type I cell
- alveolar epithelial type II cell
- aquaporin-5
- homeodomain only protein x
- intermediate cells
- transdifferentiation
HOPX acts as a tumour suppressor in various cancers. However, the regulation of HOPX in human lung cancer as well as the mechanism underlying its tumour-suppressive function has not yet been well elucidated. Here we investigated the epigenetic regulation and molecular mechanism by which HOPX exerts growth inhibitory effects. We found that HOPX was down-regulated in 12 out of 13 lung cancer cell lines and in 69 out of 120 primary lung tumours at mRNA and protein levels. Patients with lung adenocarcinoma (ADC) exhibited significantly more positive staining of HOPX protein compared with lung squamous cell carcinoma (SCC) (p =0.036). Again in ADC, patients with higher HOPX expression had a significantly longer disease-free survival (p =0.001). Methylation analysis showed that down-regulation of HOPX was associated with DNA methylation (p =0.011). To analyse the function of HOPX in lung cancer cells, stable transfection with an expression vector of HOPX was performed. It turned out that HOPX inhibited tumour cell proliferation rate, migration, and invasion, and, more interestingly, forced expression of HOPX enhanced cellular senescence via activation of oncogenic Ras and the downstream MAPK pathway, which in turn led to decreased MDM2 and increased p21. On the contrary, knockdown of HOPX by siRNA resulted in reduced Ras activity, inactivation of the MAPK pathway, and decreased p21 levels, accompanied by reduced cellular senescence. Additionally, the HOPX-induced senescence pathway was also active in human bronchial epithelial cells. Taken together, our data suggest that down-regulation of HOPX was related to DNA methylation and that HOPX exerts tumour-suppressive activity by oncogenic Ras-induced cellular senescence in lung cancer cells.
MeSH Terms
- Adenocarcinoma
- Carcinoma, Non-Small-Cell Lung
- Carcinoma, Squamous Cell
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Cells, Cultured
- Cellular Senescence
- DNA Methylation
- Down-Regulation
- Gene Expression Regulation, Neoplastic
- Homeodomain Proteins
- Humans
- Lung Neoplasms
- Signal Transduction
- Small Cell Lung Carcinoma
- Tumor Suppressor Proteins
- ras Proteins
Keywords
- HOPX
- Ras-induced senescence
- lung cancer
- methylation