Premium
The Role of p120‐catenin and PIK3CA in Migration in Head and Neck Squamous Cell Carcinoma
Author(s) -
Kidacki Michal,
Lehman Heather L,
Welsh Patricia A,
Warrick Joshua I,
Stairs Douglas B
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.439.8
Subject(s) - head and neck squamous cell carcinoma , cancer research , gene knockdown , metastasis , suppressor , catenin , population , cell , mutation , cancer , mutant , biology , head and neck cancer , medicine , gene , wnt signaling pathway , genetics , environmental health
Over half a million people worldwide are diagnosed with head and neck squamous cell carcinoma (HNSCC). A third of the newly diagnosed patients won't survive the next five years. Additionally, approximately 15% of these patients already have distant metastases at the time of diagnosis. Therefore it is of profound interest to understand the mechanism driving HNSCC metastasis. p120‐catenin (p120ctn) is a tumor suppressor that is lost in 19% of HNSCC. PIK3CA, a gene coding for the catalytic subunit of PI3‐kinase, is mutated in 21% (E545K and H1047R being the most common mutations) and overexpressed in an additional 20% of HNSCC. Both, p120ctn loss and PIK3CA mutations individually have been shown to play a role in metastasis in a number of epithelial cancer models. Considering the frequency at which both p120ctn and PIK3CA are dysregulated in HNSCC, it is very likely that these two changes may be found in the same patients, increasing a cancer's aggressiveness. Therefore, we hypothesize that cells harboring both p120ctn down‐regulation and PIK3CA mutations may represent a more malignant cell population than the cells with either of these changes alone. The tumorigenic effects of p120ctn down‐regulation and PIK3CA mutations were tested using normal oral keratinocytes (NOK). NOK cell lines were generated by down‐regulating p120ctn alone or in conjunction with an overexpression of either of the PIK3CA mutants, E545K or H1047R. Migratory and invasive capabilities of these cell lines were assessed. Boyden chamber migration assays showed that either p120ctn knockdown or each of the PIK3CA mutations alone increased cell migration 2.5 to 3‐fold compared to the control. However, when p120ctn knockdown was coupled with either the E545K or H1047R PIK3CA mutation, the cell migration increased 4‐fold. A similar increase was observed for the invasive capabilities of these cells. Signaling pathways were interrogated to identify the mechanism(s) responsible for the observed increase in cell migration. Both phospho‐STAT3 (Y705) and active, GTP‐bound RhoA were found to be increased in NOKs with p120ctn down‐regulation or PIK3CA mutations alone. Even greater increases were detected in cell lines containing both p120ctn down‐regulation and PIK3CA mutations. We are currently testing whether these increases in phospho‐STAT3 or active RhoA are responsible for the observed increase in cell migration and whether crosstalk between these signaling pathways exists. In conclusion, both p120ctn down‐regulation and PIK3CA mutations act cooperatively to increase migration/invasion, possibly via the STAT3 or RhoA pathway.