A novel strategy of C‐<i>myc</i> oncogene in NK activity regulation not related to the W6/32 MHC class‐I epitope

Cava, Antonio La; Carbone, Ennio; Moscarella, Anna; Barcova, Maria; Salzano, Salvatore; Zappacosta, Serafino; Fontana, Silvia

doi:10.1002/ijc.2910580120

Cited by 4 publications

(3 citation statements)

References 21 publications

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“…It was shown that oncogenes, such as ras, myc, and HER2, can induce the downregulation of MHC class I surface expression, resulting in an escape from immunosurveillance (12,(24)(25)(26)(27). However, there is limited information about epigenetic and oncogenic factors for downregulation of HLA-class I.…”

Section: Discussionmentioning

confidence: 99%

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

Mimura

Shiraishi

Müeller

et al. 2013

The Journal of Immunology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Mimura

Shiraishi

Müeller

et al. 2013

The Journal of Immunology

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“…It has been shown that oncogenes, such as ras and myc, can induce the downregulation of MHC class I surface expression, resulting in an escape from immunosurveillance (Basolo et al , 1992; van ‘t Veer et al , 1993; La Cava et al , 1994; Griffioen et al , 1995; Cheng et al , 1996). Furthermore, it has been shown that HER2 can activate several signal transduction pathways, including the ras/mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways (Marmor et al , 2004).…”

Section: Discussionmentioning

confidence: 99%

Inverse correlation of HER2 with MHC class I expression on oesophageal squamous cell carcinoma

et al. 2010

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Background:As HER2 is expressed in 30% of oesophageal squamous cell carcinomas (ESCCs), T-cell-based immunotherapy and monoclonal antibodies targeted against HER2 are attractive, novel approaches for ESCCs. However, it was shown that there is an inverse correlation between HER2 and MHC class I expression on tumours. Thus, the correlation between HER2 and MHC class I expressions on ESCC was evaluated.Methods:Expressions of MHC class I and HER2 in ESCC tissues (n=80) and cell lines were assessed by immunohistochemistry, fluorescence in situ hybridisation (FISH), and flow cytometry. We investigated whether HER2 downregulation with small interfering RNA (siRNA) in ESCC cell lines could upregulate the expression of MHC class I and the antigen presentation machinery components, and could increase their sensitivity for tumour antigen-specific CTLs.Results:There was an inverse correlation between HER2 and MHC class I expressions in both tumour tissues and cell lines. Downregulation of HER2 with siRNA resulted in the upregulation of MHC class I expression, leading to increased CTL recognition by tumour antigen-specific CTLs.Conclusion:HER2-overexpressing ESCC tumour cells showed a reduced sensitivity for CTLs through the downregulation of MHC class I.

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“…The sensitization can be reversed by reintroduction of MHC class I molecules by transfection. In other types of cells, c-Myc increases the sensitivity of target cells to NK cell-induced lysis without altering MHC class I expression, possibly by increasing the adhesiveness of NK cells to the targets (Cuomo et al, 1993;La Cava et al, 1994). Thus, the expression of oncogenes can have e ects on the target cell surface which facilitate the triggering of the cytolytic machinery of NK cells during NK cell-target cell interaction.…”

Section: Introductionmentioning

confidence: 99%

c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors

et al. 1999

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The contact of natural killer (NK) cells with foreign cells and with certain virus-infected or tumor cells triggers the cytolytic machinery of NK cells. This triggering leads to exocytosis of the cytotoxic NK cell granules. The oncoproteins c-Myc and E1A render cells vulnerable to NK cell mediated cytolysis yet the mechanisms of sensitization are not well understood. In a model where foreign cells (rat ®broblasts) were cocultured with human IL-2 activated NK cells, we observed that NK cells were capable of e ciently killing their targets only if the cells overexpressed the oncogene c-Myc or E1A. Both the parental and the oncogene expressing ®broblasts similarly triggered phosphoinositide hydrolysis in the bound NK cells, demonstrating that NK cells were cytolytically activated in contact with both resistant parental and oncogene expressing sensitive target ®broblasts. The cell death was independent of wild-type p53 and was not inhibited by an anti-apoptotic protein E1B19K. These results provided evidence that c-Myc and E1A activated the NK cell induced cytolysis at a post-triggering stage of NK cell-target cell interaction. In consistence, the c-Myc and E1A overexpressing ®broblasts were more sensitive to the cytolytic e ects of isolated NK cellderived granules than parental cells. The data indicate that oncogenes activate the cytotoxicity of NK cell granules. This mechanism can have a role in directing the cytolytic action of NK cells towards the virus-infected and cancer cells.

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A novel strategy of C‐myc oncogene in NK activity regulation not related to the W6/32 MHC class‐I epitope

Cited by 4 publications

References 21 publications

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

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

Inverse correlation of HER2 with MHC class I expression on oesophageal squamous cell carcinoma

c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors

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