The high‐mobility group A1‐estrogen receptor β nuclear interaction is impaired in human testicular seminomas

Abstract

It is well established that estrogens participate in the control of normal spermatogenesis and endogenous or environmental estrogens are involved in pathological germ cell proliferation including testicular germ cell tumors. The effects of estrogen are now known to be mediated by estrogen receptor-α (ERα) and ERβ subtypes, but only ERβ has been found in human germ cells of normal testis. However, its expression was markedly diminished in human testicular seminomas. The expression and the possible interaction of ERβ and HMGA1 were studied in normal germ cells and in human testicular seminomas. GC1 and TCam-2 germ cell lines, were used; in addition, a tissue micro-array (TMA) was built using the most representative areas from 35 cases of human testicular seminomas. The expression and the interaction of ERβ and HMGA1 were observed by using immunoprecipitation and Western blot analyses in combination with immunocytochemistry and immunofluorescence analyses. Here, we show that ERβ interacts with HMGA1 in normal germ cells, while down regulation of ERβ associates with transcriptional co-regulator HMGA1 over-expression and cytoplasmic localization both in human testicular seminomas and in TCam-2 cell line. In addition, we show that 17β-oestradiol induces an HMGA1 increased cytoplasmic expression associated to an ERβ down-regulation in TCam-2 cell line. Taken together, our results suggest that exposure to estrogens or estrogen-mimics, in some as of yet undefined manner, diminishes the ERβ-mediated growth restraint in human testicular seminoma, probably due to the HMGA1 cytoplasmic delocalization associated with ERβ down-regulation.

GPR30 is a Potential Therapeutic Target in Human Carcinoma in situ and Seminomas

“…First, the down-regulation of ER, observed in seminomas, was in accordance with our previously published data, and from animal models and human cell culture studies suggesting that ER may control cell proliferation during germ cells cancer progression [7,8,[21][22][23][24] . These considerations induce to hypothesize that…”

“…After activation, these receptors, in association with various coactivators as RNF4 [5,6] and repressors as PATZ1 [7][8][9][10] , act as nuclear transcription factors for targeted genes [11] . It has been well documented in literature that ER is instead down regulated in seminomas and embryonal cell carcinomas [7,12,13] .…”

“…The affected spermatogonia or their descendants may then be able to escape normal cell cycle regulation and be at a higher risk of undergoing malignant transformation [8] .…”

“…Recently, we have shown that ER interacts with HMGA1 and PATZ1 in normal germ cells, while down regulation of ERβ is concomitant with transcriptional coregulators HMGA1 and PATZ1 over-expression and cytoplasmic localization both in human testicular seminomas and in TCam-2 seminoma cell line [7][8][9][10] . We also observed that 17-oestradiol induces an HMGA1 increased cytoplasmic expression correlates with an ER down-regulation in TCam2 cell line [8] .…”

New perspective on molecular markers as promising therapeutic targets in germ cell tumors

“…Diagnosis is usually based on identification of histological subgroups. In last years, many potential therapeutic targets has been discovered, including SOX2, SOX17, HMGA1, and HMGA 2, Aurora B, PATZ1, GPR30 and others (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Promising molecules capable to selectively target neoplastic cells, that are, serine-threonine kinases, TKs, HMGAs, GPR30 antagonist, proangiogenic factors inhibitors, and micro-RNAs already under clinical evaluation will open a new scenario for TGCTs treatment.…”