The MAPK Pathway Is a Predominant Regulator of HLA-A Expression in Esophageal and Gastric Cancer

Abstract

Downregulation of HLA class I expression may contribute to a poor prognosis in cancer patients. There is limited information about epigenetic and oncogenic regulation of HLA class I, and multiple mechanisms may be involved. In the current study, we examined the relationship between the HER2-signaling pathway (MAPK and PI3K-Akt) and the expression of HLA class I and Ag-processing machinery (APM) components. A panel of gastric and esophageal cancer cell lines was treated with wortmannin as an Akt-signal inhibitor; the MAPK signal inhibitor PD98059; lapatinib, which inhibits both the epidermal growth factor receptor and HER2 tyrosine kinase; or siRNA for MAPK. The levels of HER2-signaling molecules, APM components, and HLA class I were evaluated by Western blot, quantitative PCR, and flow cytometry. Resected gastric tumor tissues (n = 102) were analyzed for p-Erk and HLA class I expression by immunohistochemistry. As a result, inhibition of the MAPK pathway induced upregulation of HLA-A02 and HLA-A24 expression in parallel with an increase in APM components and enhanced target sensitivity to tumor Ag–specific CTL lysis. HLA-A expression was predominantly regulated by the MAPK pathway, but it was also influenced, in part, by the Akt pathway. There was a strong inverse correlation between p-Erk expression and HLA class I expression in clinical tumor samples. In conclusion, HLA-A expression is predominantly regulated by the MAPK pathway in gastric and esophageal cancer.

Trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules through engagement of natural killer cells and stimulation of IFNγ secretion

“…Further, our finding that treatment with the HER2 kinase inhibitor lapatinib alone did not increase but in fact decreased HLA-ABC expression supports lack of an inverse correlation between HER2 kinase activity and HLA-ABC expression. Whereas inhibition of the MAPK pathway, which is downstream of HER2, may increase HLA-ABC expression, as reported by others, 35 treatment of cells with lapatinib can inhibit multiple pathways downstream of HER2 in addition to the MAPK pathway, one of which is the STAT1 pathway. Indeed, we found that the decrease in HLA-ABC expression induced by lapatinib was accompanied by a decrease in the level of phosphorylated STAT1.…”

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

“…Most of the studies have shown that MEK inhibition can increase the expression of intrinsic and IFN-γ-induced HLA/ MHC I/II in cancer cell lines, including melanoma, mesothelioma, prostate, gastric, and esophageal cancer cell lines [103][104][105]. Similarly to BRAF inhibition, treatment of mutant melanoma cell lines with MEK inhibition enhances the expression of melanoma-differentiation antigens [92] and decreases the production of IL-10, IL-6, and VEGF [91].…”

Mitogen-Activated Protein Kinase Signal Transduction in Solid Tumors

“…Through gene expression, knockdown, chemotherapeutic agents, observation of biologic effect, they identified that over-expression of the p38γMAPK led to marked cell cycle arrest in G2/M phase. What's more, they said the main function of p38γ MAPK in breast cancer was to maintain the oncogenic properties rather than to promote cancer progression (Mimura et al, 2013). All these indicate that p38γ MAPK is a promising target for the design of targeted therapies for basal-like breast cancer.…”

“…In other ways, Kousaku Mimura.et.al proclaimed the MAPK pathway regulated HLA-A expression in gastric cancer (Mimura et al, 2013), while reduced expression of HLA class I on tumors is often associated with disease progression and poor prognosis in diverse human tumors.…”