Parathyroid Hormone-Related Protein Is an Essential Growth Factor for Human Clear Cell Renal Carcinoma and a Target for the von Hippel-Lindau Tumor Suppressor Gene

Massfelder, Thierry; Lang, Hervé; Schordan, Eric; Lindner, Véronique; Rothhut, Sylvie; Welsch, Sandra; Simon‐Assmann, Patricia; Barthelmebs, Mariette; Jacqmin, Didier; Helwig, Jean-Jacques

doi:10.1158/0008-5472.can-03-1968

Cited by 70 publications

(98 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…33 The present study reveals that VHL-mediated apoptosis of C6 glioma cells is accompanied by downregulation of Bcl-2. VHL is a multifunctional tumor suppressor protein exerting effects on hormone levels, 34 the extracellular matrix, [35][36][37] cell differentiation 38 and growth, 39 protease and protease inhibitor secretion, 40 the cytoskeleton and cell motility and invasiveness, mRNA stability, 41 the cell cycle, 42 and cell signaling, 43 all of which may play a role in the antitumour activity of VHL.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas

et al. 2005

View full text Add to dashboard Cite

The von Hippel-Lindau tumor suppressor protein (pVHL) suppresses tumor formation by binding the a subunits of hypoxiainducible-factors responsible for stimulating tumor angiogenesis and glycolysis, and targeting them for ubiquitination and proteasomal destruction. Loss of pVHL leads to tumorigenesis and development of sporadic renal cell carcinomas and central nervous system hemangioblastomas. In the present study, we investigated whether engineered overexpression of pVHL in C6 glioma cells, which already express endogenous pVHL, would suppress the tumorigenicity of this particular tumor cell type. C6 cells overexpressing VHL displayed a reduced growth rate (70% inhibition) compared to the parental cell line when subcutaneously implanted in athymic (nu/nu) mice. Growth inhibition was associated with a 50% reduction in the number of tumor vessels and a 60% increase in tumor cell apoptosis, due in part to downregulation of HIF-1, VEGF, and the antiapoptotic factor Bcl-2, respectively. Gene transfer of VHL suppressed the growth of established C6 gliomas, and synergized with antisense HIF-1 to completely eradicate tumors. The data suggest that VHL gene therapy and/or agents that increase VHL expression could have utility in the treatment of gliomas, particularly when combined with agents that inhibit the expression or function of HIF-1.

show abstract

Section: Discussionmentioning

confidence: 99%

Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Protein extractions and membrane preparations were performed as described (Massfelder et al, 2004). Membranes were incubated overnight at 4 1C with the appropriate dilution of the following primary antibodies: anti-Akt (1:250; Millipore, Molsheim, France), anti-phospho-Akt (1:150; Ozyme, Cell Signaling local distributor, Saint-Quentin-en-Yvelines, France), anti-NF-B (1:2000; Millipore), anti-phospho-NF-kB (1:250; Ozyme), anti-glycogen synthase kinase-3a/b (1:1000; Millipore), anti-phospho-glycogen synthase kinase-3a/b (Ser21/9 ; 1:500; Millipore) anti-Erk1/2 (1:1000; Ozyme), anti-phospho-Erk1/2 (1:1000; Millipore), anti-glyceraldehyde-3-phosphate-dehydrogenase (1:500; Millipore), anti-a-tubulin (1:500; Abcam, Paris, France), anti-b-actin (1:500; Millipore), anti-paxillin (1:500; Invitrogen), anti-fibronectin (1:500; Ozyme), anti-tenascin-C (1:500; Ozyme), anti-MMP-9 (1:500; Millipore), and anti-Lim1 (1:500, Millipore).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…In all, 5 mg of total RNA were reverse transcribed in a reaction buffer (Invitrogen) and non-specific primer p(dT) 15 Cell density CCC cell proliferation was assessed by counting adherent cells, as described (Massfelder et al, 2004). RCC cells were seeded in 24-well plates (20 000 cells/ml), grown for 24 h, and then transiently transfected for 24-96 h with various concentrations of siRNAs expressing vector targeting Lhx1, siCtl or vehicle (Ctl).…”

Section: Real-time Quantitative Reverse Transcription-pcr Analysismentioning

confidence: 99%

“…A total of 10 million 786-0 cells were injected subcutaneously into the skin of 4-week-old athymic male mice (SWISS nu-/nu-; Charles River Laboratories, l 0 Arbresle, France). Tumor volumes were measured as previously described (Massfelder et al, 2004).We begun drug injections in the two groups when 786-0 tumors had grown to an overall volume of 100 mm 3 . The protocol was injection of siLhx1 ('siRNA in vivo ready' Lhx1 s8165 (exon 2) or s8166 (exon1) targeting the Lhx1 RNA) intra tumoral (iTu) at 1 nmol per mouse three times a week, the control groups receiving the siCtl negative or the vehicle alone (PBS) at the same time period.…”

Section: Xenograft Tumor Modelmentioning

confidence: 99%

See 1 more Smart Citation

LIM-class homeobox gene Lim1, a novel oncogene in human renal cell carcinoma

et al. 2010

View full text Add to dashboard Cite

“…Güncel bilgiler paratiroid hormonu benzeri peptidlerin ekspresyonunun vahşi tip VHL proteini tarafından baskılandığını ve bu peptidlerin RHK için olası büyüme faktörleri olabileceğini düşündürmektedir. Bu durum hiperkalsemisi olan RHK'lı hastaların normal serum kalsiyum düzeyi olan hastalara göre progresyona bağlı ölümlerde 1,78 kat artmış göreceli riski olması gözleminin kısmen açıklayabilmektedir (16). Hiperkalsemi belirtileri çoğunlukla özgül değildir ve bulantı, kusma, iştahsızlık, halsizlik ile azalmış derin tendon reflekslerini içermektedir.…”

Section: Hiperkalsemiunclassified

Renal Hücreli Kanserde Paraneoplastik Sendromlar

İzol¹,

Kaplan²

2014

uob

View full text Add to dashboard Cite

Genitoüriner kanserler arasında renal hücreli karsinom, hastaların yaklaşık üçte birinde paraneoplastik sendroma ait semptom ve bulguların görülebilmesiyle kendini gösteren bir patolojidir. Renal hücreli karsinom ile ilgili paraneoplastik sendromlar konstitüsyonel semptomları (örneğin; ateş, kaşeksi ve kilo kaybı) ve bunun yanı sıra spesifik metabolik ve biyokimyasal anormallikleri (örneğin; hiperkalsemi, nonmetastatik hepatik disfonksiyon, amiloidoz vb.) içermektedir. Paraneoplastik sendrom varlığı ne metastatik hastalık işareti ne de kötü prognoz göstergesidir. Renal hücreli karsinom ile ilgili paraneoplastik sendromların patofizyolojisi ve biyolojisinin anlaşılmasıyla birlikte, konstitüsyonel semptomlar veya metabolik anormallikler primer veya tekrarlayan hastalığın ilk belirtisi olabilir. Bu hastalarda, paraneoplastik sendromların doğru tanısı ve yönetimi hastaların palyatif tedavisinde önemli olabilir. RHK ile ilgili kaşeksi, ateş, karaciğer fonksiyon bozukluğu, anemi ve amiloidoz gibi paraneoplastik belirtilerin patofizyolojisi henüz tam olarak aydınlatılamamıştır. Hiperkalsemi dışındaki paraneoplastik sendromlarda geleneksel medikal tedaviler nadiren faydalıdır. Erken tanı ve etkin tedavi bu hastaların yaşam kalitesini ve prognozunu değiştirebilir. Bu derlemede, renal hücreli karsinom ile ilgili birçok paraneoplastik sendromun ortaya çıkış mekanizmalarıyla birlikte, bunların klinik yansımalarını ve bu önemli bozukluklar için mevcut tedavi seçeneklerini tartışacağız. (Üroonkoloji Bülteni 2014;13:130-134) Anah tar Ke li me ler: Paraneoplastik sendrom, renal hücreli kanser, hiperkalsemi Renal cell carcinoma which is among genitourinary cancers is a pathology presenting with signs and symptoms of paraneoplastic syndrome in almost one third of the affected patients. The paraneoplastic syndromes associated with renal cell carcinoma include constitutional symptoms (ie, fever, cachexia, and weight loss), as well as specific metabolic and biochemical abnormalities (ie, hypercalcemia, nonmetastatic hepatic dysfunction, amyloidosis, etc). The presence of a paraneoplastic syndrome in a patient with renal cell carcinoma is neither a marker of metastatic disease nor necessarily indicative of a poor prognosis. The importance of understanding the pathophysiology and biology behind the many paraneoplastic syndromes associated with renal cell carcinoma lies in the fact that the presence of these protean symptoms may be the initial presentation of either primary or recurrent disease. In these patients, the accurate diagnosis and management of paraneoplastic syndromes may be important in palliative management. Pathophysiology of paraneoplastic symptoms of RCC such as cachexia, fever, hepatic dysfunction, anemia, and amyloidosis, remains incomplete. Except for hypercalcemia, conventional medical therapies are seldom helpful in the treatment of paraneoplastic symptoms. An early diagnosis and effective treatment might improve quality of life and alter prognosis of these patients. In this review, we will describe the proposed...

show abstract

Parathyroid Hormone-Related Protein Is an Essential Growth Factor for Human Clear Cell Renal Carcinoma and a Target for the von Hippel-Lindau Tumor Suppressor Gene

Abstract: ABSTRACT

Cited by 70 publications

References 40 publications

Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas

Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas

LIM-class homeobox gene Lim1, a novel oncogene in human renal cell carcinoma

Renal Hücreli Kanserde Paraneoplastik Sendromlar

Contact Info

Product

Resources

About