Dataset Information

Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma.

ABSTRACT:

Background

The aggressiveness of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 translocation RCC [Xp11.2 tRCC]) is age-dependent, which is similar to the overall trend of reproductive endocrine hormones. Therefore, this study focused on the effect and potential mechanism of androgen and androgen receptor (AR) on the progression of Xp11.2 tRCC.

Methods

The effects of androgen and AR on the proliferation and migration of Xp11.2 tRCC cells were first evaluated utilising Xp11.2 tRCC cell lines and tissues. Because Transcription factor enhancer 3 (TFE3) fusion proteins play a key role in Xp11.2 tRCC, we focused on the regulatory role of AR and TFE3 expression and transcriptional activity.

Results

When Xp11.2 tRCC cells were treated with dihydrotestosterone, increased cell proliferation, invasion and migration were observed. Compared with clear cell RCC, the positive rate of AR in Xp11.2 tRCC tissues was higher, and its expression was negatively associated with the progression-free survival of Xp11.2 tRCC. Further studies revealed that AR could positively regulate the transcriptional activity of TFE3 fusion proteins by small ubiquitin-related modifier (SUMO)-specific protease 1, inducing the deSUMOylation of TFE3 fusion. On the other hand, UCHL1 negatively regulated by AR plays a role in the deubiquitination degradation of the PRCC-TFE3 fusion protein. Therefore, the combination of the AR inhibitor MDV3100 and the UCHL1 inhibitor 6RK73 was effective in delaying the progression of Xp11.2 tRCC, especially PRCC-TFE3 tRCC.

Conclusions

Androgen and AR function as facilitators in Xp11.2 tRCC progression and may be a novel therapeutic target for Xp11.2 tRCC. The combined use of AR antagonist MDV3100 and UCHL1 inhibitor 6RK73 increased both the SUMOylation and ubiquitination of the PRCC-TFE3 fusion protein.

SUBMITTER: Liu N

PROVIDER: S-EPMC9029019 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma.

Liu Ning N Chen Yi Y Yang Lei L Shi Qiancheng Q Lu Yanwen Y Ma Wenliang W Han Xiaodong X Guo Hongqian H Li Dongmei D Gan Weidong W

Clinical and translational medicine 20220401 4

<h4>Background</h4>The aggressiveness of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 translocation RCC [Xp11.2 tRCC]) is age-dependent, which is similar to the overall trend of reproductive endocrine hormones. Therefore, this study focused on the effect and potential mechanism of androgen and androgen receptor (AR) on the progression of Xp11.2 tRCC.<h4>Methods</h4>The effects of androgen and AR on the proliferation and migration of Xp11.2 tRCC cells w ...[more]

PMID: 35452181

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Project description:BACKGROUND:To investigate the contrast-enhanced ultrasound (CEUS) findings of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2/TFE3) in adult patients by comparison with those of clear cell RCC (ccRCC) and papillary RCC (pRCC). METHODS:In total, 110 patients (110 renal masses) who underwent CEUS examinations were enrolled in this study. The cases included 18 Xp11.2/TFE3 RCCs, 60 ccRCCs and 32 pRCCs. All masses were confirmed by operative pathology. The CEUS imaging data of these patients were retrospectively analysed by two readers. The conventional US and CEUS features of Xp11.2/TFE3 RCC were compared with those of ccRCC and pRCC. RESULTS:The age of the patients with Xp11.2/TFE3 RCC ranged from 20 to 68 years, with a mean age of 38.3 ± 16.3 years and a slight female predominance. The weighted kappa value that interprets the concordance between the interobserver agreement of the US and CEUS features ranged from 0.61 to 0.89. On conventional US and CEUS imaging of Xp11.2/TFE3 RCCs, the tumours were hypoechoic (6/18, 33.3%), isoechoic (8/18, 44.4%), and hyperechoic (4/18, 22.2%). The cystic component was present in 5 cases (27.8%), calcification was present in 9 cases (50.0%), and colour flow signal was present in 7 cases (38.9%). Most cases showed simultaneous wash-in (11/18, 61.1%); the peak enhancement showed hypoenhancement (6/18, 33.3%), isoenhancement (10/18, 55.6%), and hyperenhancement (2/18, 11.1%); most cases exhibited heterogeneous enhancement (12/18, 66.7%) and fast- or simultaneous-out (16/18, 88.9%); and a pseudocapsule was present in 6 cases (33.3%). In the multivariate logistic regression analysis, calcification and lower peak enhancement were more likely to be present in Xp11.2/TFE3 RCC than in ccRCC (P < 0.05), and younger age and relatively high peak enhancement were more likely to be present in Xp11.2/TFE3 RCC than in pRCC (P < 0.05). The calcification combined peak enhancement model differentiated Xp11.2/TFE3 RCC from ccRCC, and the age combined peak enhancement model differentiated Xp11.2/TFE3 RCC from pRCC with an AUC, a sensitivity and a specificity of 0.896, 94.4% and 73.3% and 0.786, 50.0% and 100.0%, respectively. CONCLUSIONS:The specific CEUS features combined with demographic information and clinical symptoms may be helpful for differentiating Xp11.2/TFE3 RCC from ccRCC and pRCC.

Project description:ObjectiveThis study aims to establish an effective predictive model for predicting Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma (TFE3-RCC) and develop optimal therapeutic strategies.MethodsData from 4961 patients diagnosed with renal cell carcinoma at two medical centers in China were retrospectively analyzed. A cohort of 1571 patients from Zhejiang Provincial People's Hospital (Ra cohort) was selected to construct the model. Another cohort of 1124 patients from the Second Affiliated Hospital of Zhejiang Chinese Medical University was used for external validation (the Ha cohort). All patients with TFE3-RCC in both cohorts were included in the Ta cohort for the prognostic analysis. Univariate and multivariate binary logistic regression analyses were performed to identify independent predictors of the predictive nomogram. The apparent performance of the model was validated. Decision curve analysis was also performed to assess the clinical utility of the developed model. Factors associated with progression and prognosis in the Ta cohort were analyzed using the log-rank method, and Cox regression analysis and Kaplan-Meier survival curves were used to describe the effects of factors on prognosis and progression.ResultsUnivariate and multivariate logistic regression analyses demonstrated that age, sex, BMI, smoking, eosinophils, and LDL were independent predictors of TFE3-RCC. Therefore, a predictive nomogram for TFE3-RCC, which had good discriminatory power (AUC = 0.796), was constructed. External validation (AUC = 0.806) also revealed good predictive ability. The calibration curves displayed good consistency between the predicted and observed incidences of TFE3-RCC. Invasion of regional lymph nodes, tyrosine kinase inhibitors, and surgical methods were independent factors associated with progression. Tyrosine kinase inhibitors are independent prognostic factors.ConclusionThis study not only proposed a high-precision clinical prediction model composed of various variables for the early diagnosis of Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma but also optimized therapeutic strategies through prognostic analysis.

Project description:BackgroundXp11.2 or TFE3 translocation renal cell carcinomas (RCC) and alveolar soft part sarcoma (ASPS) are characterized by chromosome translocations involving the Xp11.2 breakpoint resulting in transcription factor TFE3 gene fusions. The most common translocations documented in TFE3 RCCs are t(X;1) (p11.2;q21) and t(X;17) (p11.2;q25) which leads to fusion of TFE3 gene on Xp11.2 with PRCC or ASPL respectively. TFE3 immunohistochemistry (IHC) has been inconsistent over time due to background staining problems in part related to fixation issues. Karyotyping to detect TFE3 gene rearrangement requires typically unavailable fresh tissue. Reverse transcriptase-polymerase chain reaction (RT-PCR) is generally very challenging due to degradation of RNA in archival material. The study objective was to develop and validate a TFE3 break-apart fluorescence in situ hybridization (FISH) assay to confirm Xp11 translocation RCCs and ASPS.MethodsRepresentative sections of formalin-fixed paraffin-embedded tissue blocks were selected in 40 possible cases. Approximately 60 tumor cells were analyzed in the targeted region. The validation of TFE3 FISH was done with 11 negative and two positive cases. Cut off for a positive result was validated as >7.15 % positive nuclei with any pattern of break-apart signals. FISH evaluation was done blinded of the immunohistochemical or karyotype data.ResultsThree out of forty cases were positive for the TFE3 break-apart signals by FISH. The negative cases were reported as clear cell RCC with papillary features (10), clear cell RCC with sarcomatoid areas (2), Papillary RCC with clear cell areas (9), Chromophobe RCC (2), RCC, unclassified type (3) and renal medullary carcinoma (1). 3 of the negative cases were consultation cases for renal tumor with unknown histology. Seven negative cases were soft tissue tumor suspicious for ASPS.ConclusionOur study validates the utility of TFE3 break-apart FISH on formalin-fixed paraffin-embedded tissue sections for diagnosis and confirmation of Xp11.2 translocation RCCs and ASPS.

Dataset Information

Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma.

Background

Methods

Results

Conclusions

Publications

Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma.

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