Liprin-α1 modulates cancer cell signaling by transmembrane protein CD82 in adhesive membrane domains linked to cytoskeleton.
BACKGROUND
PPFIA1 is located at the 11q13 region commonly amplified in cancer. The protein liprin-α1 encoded by PPF1A1 contributes to the adhesive and invasive structures of cytoskeletal elements and is located at the invadosomes in cancer cells. However, the precise mechanism of liprin-α1 function in cancer progression has remained elusive.


METHODS
Invasion regulating activity of liprin-α1 was examined by analyzing the functions of squamous cell carcinoma of head and neck (HNSCC) cell lines in three-dimensional collagen I after RNAi mediated gene knockdown. Transcriptome profiling and Gene Set Enrichment Analysis from HNSCC and breast cancer cells were used to identify expression changes relevant to specific cellular localizations, biological processes and signaling pathways after PPFIA1 knockdown. The significance of the results was assessed by relevant statistical methods (Wald and Benjamini-Hochberg). Localization of proteins associated to liprin-α1 was studied by immunofluorescence in 2D and 3D conditions. The association of PPFIA1 amplification to HNSCC patient survival was explored using The Cancer Genome Atlas data.


RESULTS
In this study, we show that liprin-α1 regulates biological processes related to membrane microdomains in breast carcinoma, as well as protein trafficking, cell-cell and cell-substrate contacts in HNSCC cell lines cultured in three-dimensional matrix. Importantly, we show that in all these cancer cells liprin-α1 knockdown leads to the upregulation of transmembrane protein CD82, which is a suppressor of metastasis in several solid tumors.


CONCLUSIONS
Our results provide novel information regarding the function of liprin-α1 in biological processes essential in cancer progression. The results reveal liprin-α1 as a novel regulator of CD82, linking liprin-α1 to the cancer cell invasion and metastasis pathways.
['Pehkonen|Henna|H|', 'Lento|Mira|M|', 'von Nandelstadh|Pernilla|P|', 'Filippou|Artemis|A|', 'Grénman|Reidar|R|', 'Lehti|Kaisa|K|', 'Monni|Outi|O|']
D048868:Adaptor Proteins, Signal Transducing D000268:Adhesiveness D001943:Breast Neoplasms D045744:Cell Line, Tumor D003599:Cytoskeleton D055785:Gene Knockdown Techniques D006801:Humans D051861:Kangai-1 Protein D021962:Membrane Microdomains D009362:Neoplasm Metastasis D015398:Signal Transduction D000077195:Squamous Cell Carcinoma of Head and Neck
Liprin-α1 CD82 PPFIA1 Invasion Breast cancer Head and neck cancer RNA sequencing Three-dimensional cell culture