Investigation of EGFR/pi3k/Akt signaling pathway in seminomas

ABSTRACT

Activation of the receptor for epidermal growth factor (EGFR) in some testicular tumors activates several signaling pathways. Some components of these pathways are phosphorylated or mutated in testicular germ tumors (TCGT), including EGFR, Kirstein ras oncogen (KRAS) and cell surface protein of the germ cell (KIT). The latter two activate RAF ⁄MEK⁄ERK and PI3 K⁄AKT, and interconnect with the EGFR/pI3 k/Akt pathway. We investigated the expression of EGFR/pI3 k/Akt pathway proteins in seminomas and in their precursor lesion, germinal cell neoplasia in situ (GCNIS) and related genetic mutations. We used immunohistochemistry for pEGFR, pI3 k and pAkt expression with a scoring system for 46 seminoma surgical specimens: 36 classical and 10 GCNIS. In 17 samples, the mutations of EGFR (exons 19 − 21), KIT (exons 11, 17) and KRAS (exons 2, 3) were investigated using qPCR and sequencing. Of the 36 seminomas studied, 22 (61%) expressed pEGFR. Ten samples exhibited high scores for pEGFR, pI3 k and pAkt. In 5 of 17 cases (33%) some mutation was exhibited in the exons studied: 21 of EGFR (2), 17 of EGFR (1), 3 of KRAS (1) and 11 of KIT (1). Six cases exhibited nuclear translocation of EGFR; of these, four exhibited mutations of EGFR, KRAS and KIT. Eight of ten of the GCNIS expressed a high pEGFR score (80%). In 2 of 6 cases (33%), mutation was detected in exon 21 of EGFR and one smear showed EGFR translocation to the nucleus. The translocation represents a subpopulation with worse prognosis for TCGT. The EGFR/pI3 k/Akt signaling pathway is linked to TDRG1, which regulates chemosensitivity to cisplatin; this is a mechanism of resistance to treatment. TDRG1 and the EGFR/pI3 k/pAkt pathway could be therapeutic targets for seminomas resistant to cisplatin.

KEYWORDS:

• Epidermal growth factor receptor (EGFR)
• cell-surface protein of the germ cell (KIT)
• kirstein ras oncogen (KRAS)
• phosphatidylinositol 3-kinase pathway (pI3K/AKT)
• seminomas
• TDRG1
• testicular germ tumors

Disclosure statement

The authors declare no conflict of interest

Additional information

Funding

This work was supported by the The Fertility Laboratory in the development and application of Biochemical Technology in the ICSI era [Proyecto UBACYT 01/O009].