Expression levels of hnRNP G and hTra2‐beta1 correlate with opposite outcomes in endometrial cancer biology

Abstract

HnRNP G is a member of heterogeneous nuclear ribonucleoprotein (hnRNP) family with potent tumor suppressive activities. Human transformer-2-beta1 (hTra2-beta1) belongs to the arginine-serine rich like proteins and is found over-expressed in various human cancers. It was recently shown that hnRNP G and hTra2-beta1 exert antagonistic effects on alternative splicing. In our study we explored the impact of these two factors in tumor biology of endometrial cancer (EC). EC tissues (n 5 139) were tested for hnRNP G and hTra2-beta1 expression on mRNA level by real time PCR and on protein level by immunohistochemistry. HTra2-beta1 mRNA level was found being induced in advanced International Federation of Gynecology and Obstetrics (FIGO) stages (p 5 0.016). HnRNP G protein nuclear expression was found more prominent in patients without distant organ metastases (p 5 0.033) and in FIGO Stages I/II group (p < 0.001). HTra2-beta1 protein nuclear levels were elevated in poorly differentiated (p 5 0.044) and lymph node metastases (p 5 0.003) cancers. Kaplan-Meier survival curves revealed that elevated hnRNP G mRNA (p 5 0.029) and protein (p 5 0.022) levels were associated with a favorable patient outcome. Multivariate Cox-regression analyses identified nuclear hnRNP G level [hazard ratio (HR) 0.468, p 5 0.026) as well as hTra2-beta1 level (hazard ratio 5.760, p 5 0.004) as independent prognostic factors for EC progression-free survival. Our results indicate that the antagonistic functional effects of hnRNP G and hTra2-beta1 on alternative splicing correlate directly to their opposite clinical effects on EC patient outcome.Endometrial cancer (EC) is the most common gynecological malignancy in developed countries and occurs mostly among perimenopausal and postmenopausal women. It is classified into two types. 1 Type I EC is estrogen-related endometrioid subtype, usually low grade and represents the vast majority of EC. Type II EC is generally estrogen-independent and comprises high grade tumors e.g., serous or clear-cell histology. In contrast to Type I, Type II EC occurs in older women and represents only up to 10% of cases. 2 The underlying molecular pathogenesis of both EC subtypes, however, is poorly understood. The transition from normal endometrium to invasive cancer is thought to involve a stepwise accumulation of genetic alterations favouring cell dedifferentiation and proliferation. 3 This is reflected by molecular alterations like alternative splicing pattern change leading to increasing numbers of coexisting estrogen receptor a (ESRa) mRNA isoforms in endometrial adenocarcinoma. 4 Furthermore, loss of ESRa expression is associated with poor patient outcome in EC. 5 Alternative splicing is recognized as a pivotal mechanism in regulation of gene expression and associated to tumorigenesis and metastasis of a wide variety of human cancers. [6][7][8] Regulation of alternative splicing is mediated by specific functional interactions of cis-acting splicing elements and trans-acting factors. Among the latter ones, two importan...

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Characterization of the RNA recognition mode of hnRNP G extends its role in SMN2 splicing regulation

“…Alternatively, hnRNP G and Tra2-β1 could also antagonize the binding of each other to RNA (20) (Figure 7A). This later mode of action would explain the opposite effects observed for these two proteins on endometrial cancer progression (59). As illustrated in Figure 4C, we also observed a competition between these two proteins when both Tra2-β1 and hnRNP G RRMs are bound to the SMN2 derived 5′-UCAAAAAGAAG-3′ RNA.…”

Gene expression profile analysis identifies metastasis and chemoresistance-associated genes in epithelial ovarian carcinoma cells

“…RBMX gene, also known as HnRNP G , is a member of heterogeneous nuclear ribonucleoprotein (hnRNP) family and can collaborate with hTra2 - beta1 (human transformer-2-beta1) as sequence-specific transacting factors to exert antagonistic effects on alternative splicing which is recognized as a pivotal mechanism in regulation of gene expression and associated to tumorigenesis and metastasis of a wide variety of human cancers [ 26 ]. It is proposed that the ratio of hnRNP G/hTra2-beta1 influenced cellular splicing preference [ 27 , 28 ]. Some researches revealed that hnRNP G-protein showed as tumor suppressor in endometrial carcinoma [ 27 ] and oral squamous cancer [ 29 ], its activity was elicited by transactivating tumor suppressor Txnip gene [ 30 ].…”

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