The microphthalmia-associated transcription factor/transcription factor E (MiT/TFE) family of transcription factors are evolutionarily conserved, basic helix-loop-helix leucine zipper (bHLH-Zip) ...transcription factors, consisting of MITF, TFEB, TFE3, and TFEC. MiT/TFE proteins, with the exception of TFEC, are involved in the development of renal cell carcinoma (RCC). Most of the MiT/TFE transcription factor alterations seen in sporadic RCC cases of MiT family translocation renal cell carcinoma (tRCC) are chimeric proteins generated by chromosomal rearrangements. These chimeric MiT/TFE proteins retain the bHLH-Zip structures and act as oncogenic transcription factors. The germline variant of
p.E318K has been reported as a risk factor for RCC. E 318 is present at the SUMOylation consensus site of MITF. The p.E318K variant abrogates SUMOylation on K 316, which results in alteration of MITF transcriptional activity. Only a few cases of
p.E318K RCC have been reported, and their clinical features have not yet been fully described. It would be important for clinicians to recognize
p.E318K RCC and consider
germline testing for undiagnosed familial RCC cases. This review outlines the involvement of the MiT/TFE transcription factors in RCC, both in sporadic and hereditary cases. Further elucidation of the molecular function of the MiT/TFE family is necessary for better diagnosis and treatment of these rare diseases.
Xp11.2 translocation renal cell carcinoma (Xp11 tRCC) is a rare sporadic pediatric kidney cancer caused by constitutively active TFE3 fusion proteins. Tumors in patients with Xp11 tRCC tend to recur ...and undergo frequent metastasis, in part due to lack of methods available to detect early‐stage disease. Here we generated transgenic (Tg) mice overexpressing the human PRCC‐TFE3 fusion gene in renal tubular epithelial cells, as an Xp11 tRCC mouse model. At 20 weeks of age, mice showed no histological abnormalities in kidney but by 40 weeks showed Xp11 tRCC development and related morphological and histological changes. MicroRNA (miR)‐204‐5p levels in urinary exosomes of 40‐week‐old Tg mice showing tRCC were significantly elevated compared with levels in control mice. MicroRNA‐204‐5p expression also significantly increased in primary renal cell carcinoma cell lines established both from Tg mouse tumors and from tumor tissue from 2 Xp11 tRCC patients. All of these lines secreted miR‐204‐5p‐containing exosomes. Notably, we also observed increased miR‐204‐5p levels in urinary exosomes in 20‐week‐old renal PRCC‐TFE3 Tg mice prior to tRCC development, and those levels were equivalent to those in 40‐week‐old Tg mice, suggesting that miR‐204‐5p increases follow expression of constitutively active TFE3 fusion proteins in renal tubular epithelial cells prior to overt tRCC development. Finally, we confirmed that miR‐204‐5p expression significantly increases in noncancerous human kidney cells after overexpression of a PRCC‐TFE3 fusion gene. These findings suggest that miR‐204‐5p in urinary exosomes could be a useful biomarker for early diagnosis of patients with Xp11 tRCC.
We generated transgenic mice overexpressing the human PRCC‐TFE3 fusion gene in renal tubular epithelial cells, as an Xp11.2 translocation renal cell carcinoma (Xp11 tRCC) mouse model. Transgenic mice showed significant levels of microRNA (miR)‐204‐5p in urinary exosomes prior to tRCC development. These findings suggest that miR‐204‐5p in urinary exosomes could be a useful biomarker for diagnosis of patients with Xp11 tRCC.
Blood and lymphatic vessels structurally bear a strong resemblance but never share a lumen, thus maintaining their distinct functions. Although lymphatic vessels initially arise from embryonic veins, ...the molecular mechanism that maintains separation of these two systems has not been elucidated. Here, we show that genetic deficiency of Folliculin, a tumor suppressor, leads to misconnection of blood and lymphatic vessels in mice and humans. Absence of Folliculin results in the appearance of lymphatic-biased venous endothelial cells caused by ectopic expression of Prox1, a master transcription factor for lymphatic specification. Mechanistically, this phenotype is ascribed to nuclear translocation of the basic helix-loop-helix transcription factor Transcription Factor E3 (TFE3), binding to a regulatory element of Prox1, thereby enhancing its venous expression. Overall, these data demonstrate that Folliculin acts as a gatekeeper that maintains separation of blood and lymphatic vessels by limiting the plasticity of committed endothelial cells.
Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3‐RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC‐TFE3 ...protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3‐RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3‐RCC cells, PRCC‐TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC‐TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil–polyamide conjugate (Chb) to target PRCC‐TFE3‐dependent transcription, and identified Chb16 as a PRCC‐TFE3‐dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient‐derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3‐RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3‐RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3‐RCC.
PRCC‐TFE3 regulates the expression of heme oxygenase 1 (HMOX1) and confers resistance to chemotherapy in Xp11.2 translocated renal cell carcinoma. A novel chlorambucil–polyamide conjugate, Chb 16, targets PRCC‐TFE3‐dependent transcription, induces senescence and growth arrest, and increases the sensitivity of TFE3‐RCC cells to genotoxic drugs.
Birt–Hogg–Dubé syndrome is an autosomal dominantly inherited disease that predisposes patients to develop fibrofolliculoma, lung cysts and bilateral multifocal renal tumors, histologically hybrid ...oncocytic/chromophobe tumors, chromophobe renal cell carcinoma, oncocytoma, papillary renal cell carcinoma and clear cell renal cell carcinoma. The predominant forms of Birt–Hogg–Dubé syndrome‐associated renal tumors, hybrid oncocytic/chromophobe tumors and chromophobe renal cell carcinoma are typically less aggressive, and a therapeutic principle for these tumors is a surgical removal with nephron‐sparing. The timing of surgery is the most critical element for postoperative renal function, which is one of the important prognostic factors for Birt–Hogg–Dubé syndrome patients. The folliculin gene (FLCN) that is responsible for Birt–Hogg–Dubé syndrome was isolated as a novel tumor suppressor for kidney cancer. Recent studies using murine models for FLCN, a protein encoded by the FLCN gene, and its two binding partners, folliculin‐interacting protein 1 (FNIP1) and folliculin‐interacting protein 2 (FNIP2), have uncovered important roles for FLCN, FNIP1 and FNIP2 in cell metabolism, which include AMP‐activated protein kinase‐mediated energy sensing, Ppargc1a‐driven mitochondrial oxidative phosphorylation and mTORC1‐dependent cell proliferation. Birt–Hogg–Dubé syndrome is a hereditary hamartoma syndrome, which is triggered by metabolic alterations under a functional loss of FLCN/FNIP1/FNIP2 complex, a critical regulator of kidney cell proliferation rate; a mechanistic insight into the FLCN/FNIP1/FNIP2 pathway could provide us a basis for developing new therapeutics for kidney cancer.
Germline mutations in a tumor suppressor gene FLCN lead to development of fibrofolliculomas, lung cysts and renal cell carcinoma (RCC) in Birt-Hogg-Dubé syndrome. TFE3 is a member of the MiTF/TFE ...transcription factor family and Xp11.2 translocations found in sporadic RCC involving TFE3 result in gene fusions and overexpression of chimeric fusion proteins that retain the C-terminal DNA binding domain of TFE3. We found that GPNMB expression, which is regulated by MiTF, was greatly elevated in renal cancer cells harboring either TFE3 translocations or FLCN inactivation. Since TFE3 is implicated in RCC, we hypothesized that elevated GPNMB expression was due to increased TFE3 activity resulting from the inactivation of FLCN.
TFE3 knockdown reduced GPNMB expression in renal cancer cells harboring either TFE3 translocations or FLCN inactivation. Moreover, FLCN knockdown induced GPNMB expression in FLCN-restored renal cancer cells. Conversely, wildtype FLCN suppressed GPNMB expression in FLCN-null cells. FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization as revealed by elevated GPNMB mRNA and protein expression, and predominantly nuclear immunostaining of TFE3 in renal cancer cells, mouse embryo fibroblast cells, mouse kidneys and mouse and human renal tumors. Nuclear localization of TFE3 was associated with TFE3 post-translational modifications including decreased phosphorylation.
Increased TFE3 activity is a downstream event induced by FLCN inactivation and is likely to be important for renal tumor development. This study provides an important novel mechanism for induction of TFE3 activity in addition to TFE3 overexpression resulting from Xp11.2 translocations, suggesting that TFE3 may be more broadly involved in tumorigenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
Renal cell carcinoma with TFEB amplification is rare and reportedly aggressive. We herein report a case of renal cell carcinoma with TFEB translocation and amplification in which ...long‐term control was achieved by multimodal therapy including a vascular endothelial growth factor ‐receptor inhibitor.
Case presentation
A 70‐year‐old man was referred to our institution for the treatment of renal cell carcinoma with multinodal metastases. Open nephrectomy and lymph node dissection were performed. Immunohistochemistry for transcription factor EB was positive, and fluorescent in situ hybridization revealed TFEB rearrangement and amplification. The diagnosis was TFEB‐translocated and ‐amplified renal cell carcinoma. VEGFA amplification was also demonstrated by fluorescent in situ hybridization. The residual and recurrent tumors were treated and controlled for 52 months by vascular endothelial growth factor‐receptor target therapy, radiation therapy, and additional surgery.
Conclusion
A good long‐term response to anti‐vascular endothelial growth factor drug therapy may be due to VEGFA amplification and subsequent vascular endothelial growth factor overexpression.
Significance The role of FLCN as a tumor suppressor in kidney cancer has been well documented, whereas the functional roles of folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1 and FNIP2) in ...kidney are unknown. In this study, we demonstrate that double inactivation of Fnip1 and Fnip2 leads to enlarged polycystic kidneys or kidney cancer, which mimics the phenotypes seen in Flcn -deficient kidneys and underscores the significance of Fnip1 and Fnip2 in kidney tumor suppression. Moreover, we found that Fnip1/Fnip2 mRNA ratios differ among organs, which may reflect tissue-specific roles for each Fnip . Our findings define Fnip1 and Fnip2 as critical components of the Flcn complex that are essential for its tumor suppressive function and will aid in the development of novel therapeutics for kidney cancer.
Folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1, FNIP2) are homologous binding partners of FLCN, a tumor suppressor for kidney cancer. Recent studies have revealed potential functions for Flcn in kidney; however, kidney-specific functions for Fnip1 and Fnip2 are unknown. Here we demonstrate that Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. We observed no detectable phenotype in Fnip2 knockout mice, whereas Fnip1 deficiency produced phenotypes similar to those seen in Flcn -deficient mice in multiple organs, but not in kidneys. We found that absolute Fnip2 mRNA copy number was low relative to Fnip1 in organs that showed phenotypes under Fnip1 deficiency but was comparable to Fnip1 mRNA copy number in mouse kidney. Strikingly, kidney-targeted Fnip1 / Fnip2 double inactivation produced enlarged polycystic kidneys, as was previously reported in Flcn -deficient kidneys. Kidney-specific Flcn inactivation did not further augment kidney size or cystic histology of Fnip1/Fnip2 double-deficient kidneys, suggesting pathways dysregulated in Flcn -deficient kidneys and Fnip1/Fnip2 double-deficient kidneys are convergent. Heterozygous Fnip1/ homozygous Fnip2 double-knockout mice developed kidney cancer at 24 mo of age, analogous to the heterozygous Flcn knockout mouse model, further supporting the concept that Fnip1 and Fnip2 are essential for the tumor-suppressive function of Flcn and that kidney tumorigenesis in human Birt–Hogg–Dubé syndrome may be triggered by loss of interactions among Flcn, Fnip1, and Fnip2. Our findings uncover important roles for Fnip1 and Fnip2 in kidney tumor suppression and may provide molecular targets for the development of novel therapeutics for kidney cancer.
PDF
