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1.
Intern Med ; 62(20): 3075-3084, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36858515

RESUMO

A 74-year-old woman was admitted with hypercalcemia and prolonged disturbance of consciousness. The left buttock to the anterior aspect of the left thigh was swollen and erythematous, with a collection of 1.0-cm large, firm, elastic nodules distributed in a zosteriform pattern in the L1-L4 region. Based on autopsy findings, a very rare case of Cobb syndrome was diagnosed due to a spinal vascular malformation at the Th12-L4 level and L5 vertebral hemangioma. Cobb syndrome-associated cutaneous metastasis extending along the same metamere was complicated by immunohistochemically proven parathyroid hormone-related protein-producing advanced bladder carcinoma in this case.


Assuntos
Carcinoma de Células Escamosas , Hipercalcemia , Síndromes Endócrinas Paraneoplásicas , Proteína Relacionada ao Hormônio Paratireóideo , Neoplasias Cutâneas , Neoplasias da Bexiga Urinária , Idoso , Feminino , Humanos , Autopsia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Diferenciação Celular , Hipercalcemia/etiologia , Proteína Relacionada ao Hormônio Paratireóideo/análise , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/secundário , Bexiga Urinária , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Síndromes Endócrinas Paraneoplásicas/etiologia , Hemangioma/complicações , Doenças da Coluna Vertebral/complicações
2.
Biomed Res Int ; 2019: 3904923, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949498

RESUMO

BACKGROUND AND AIMS: A growing body of research has demonstrated that the degeneration of chondrocytes is the primary cause of osteoarthritis (OA). Parathyroid hormone-related protein (PTHrP) can alleviate the degeneration of chondrocytes via promotion of chondrocyte proliferation and inhibition of terminal differentiation, but the underlying mechanism remains unknown. This study aimed to identify the microRNAs (miRNAs) that may target PTHrP and regulate the proliferation and terminal differentiation of chondrocytes. METHODS: Bioinformatic analysis was used to predict which miRNAs target PTHrP. We collected human knee cartilage specimens to acquire the primary chondrocytes, which we then used to test the expression and function of the targeted miRNAs. To explore the effects of miR-15a-5p on the putative binding sites, specific mimics or inhibitors were transfected into the chondrocytes. Furthermore, a dual-luciferase reporter gene assay and chondrocyte degeneration-related factors were used to verify the possible mechanism. RESULTS: The expression of PTHrP was upregulated in the OA chondrocytes, whilst miR-15a-5p was downregulated in the OA chondrocytes. A negative correlation was observed between PTHrP and miR-15a-5p. The knockdown of miR-15a-5p promoted the growth of chondrocytes and inhibited calcium deposition, whilst overexpression of miR-15a-5p reversed this trend. The effect of miR-15a-5p overexpression was neutralised by PTHrP. Dual-luciferase reporter assays revealed that PTHrP can be used as a novel targeting molecule for miR-15a-5p. CONCLUSIONS: miR-15a-5p promotes the degeneration of chondrocytes by targeting PTHrP and, in addition to helping us understand the development of OA, may be a potential biomarker of OA.


Assuntos
Condrócitos/metabolismo , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Condrócitos/patologia , Humanos , MicroRNAs/genética , Osteoartrite/genética , Osteoartrite/patologia , Proteína Relacionada ao Hormônio Paratireóideo/genética
3.
Development ; 145(11)2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29752384

RESUMO

During zebrafish fin regeneration, blastema cells lining the epidermis differentiate into osteoblasts and joint cells to reconstruct the segmented bony rays. We show that osteoblasts and joint cells originate from a common cell lineage, but are committed to different cell fates. Pre-osteoblasts expressing runx2a/b commit to the osteoblast lineage upon expressing sp7, whereas the strong upregulation of hoxa13a correlates with a commitment to a joint cell type. In the distal regenerate, hoxa13a, evx1 and pthlha are sequentially upregulated at regular intervals to define the newly identified presumptive joint cells. Presumptive joint cells mature into joint-forming cells, a distinct cell cluster that maintains the expression of these factors. Analysis of evx1 null mutants reveals that evx1 is acting upstream of pthlha and downstream of or in parallel with hoxa13a Calcineurin activity, potentially through the inhibition of retinoic acid signaling, regulates evx1, pthlha and hoxa13a expression during joint formation. Furthermore, retinoic acid treatment induces osteoblast differentiation in mature joint cells, leading to ectopic bone deposition in joint regions. Overall, our data reveal a novel regulatory pathway essential for joint formation in the regenerating fin.


Assuntos
Nadadeiras de Animais/crescimento & desenvolvimento , Calcineurina/metabolismo , Articulações/crescimento & desenvolvimento , Regeneração/fisiologia , Tretinoína/farmacologia , Peixe-Zebra/fisiologia , Animais , Diferenciação Celular/fisiologia , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Osteoblastos/citologia , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Proteína Relacionada ao Hormônio Paratireóideo/genética , Fator de Transcrição Sp7/biossíntese , Fator de Transcrição Sp7/genética , Fatores de Transcrição/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/biossíntese , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
4.
Nihon Shokakibyo Gakkai Zasshi ; 114(7): 1285-1292, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28679985

RESUMO

A 78-year-old man was referred to our hospital with suspected liver abscess. Fever and inflammatory reaction resolved after percutaneous drainage and administration of antibiotics. However, leukocyte count was remarkably increased, and hypercalcemia was noted. The liver mass was also enlarged, as observed in the follow-up abdominal CT scans. Therefore, a percutaneous needle biopsy was performed, and the histopathological findings indicated the presence of adenocarcinoma. Additional blood examination revealed high serum levels of granulocyte colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP). Lastly, the patient was diagnosed with cholangiocarcinoma producing G-CSF and PTHrP. Chemoradiotherapy with S-1 was initiated, which was partially effective. However, the patient died 134 days after initiating the therapy. Only two cases of cholangiocarcinoma producing G-CSF and PTHrP have been reported to date. Here we reported an additional case of cholangiocarcinoma producing G-CSF and PTHrP.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Colangiocarcinoma/diagnóstico por imagem , Fator Estimulador de Colônias de Granulócitos/biossíntese , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Adenocarcinoma/complicações , Adenocarcinoma/metabolismo , Idoso , Neoplasias dos Ductos Biliares/complicações , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/complicações , Colangiocarcinoma/metabolismo , Humanos , Hipercalcemia/etiologia , Masculino
5.
J Cancer Res Clin Oncol ; 143(8): 1395-1407, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28342003

RESUMO

PURPOSE: Expression of the carboxyl PTHrP region of parathyroid hormone-related protein (PTHrP) is a positive prognostic indicator in women with lung cancer, but amino PTHrP is a negative indicator in other lung cancer patients. This project investigated whether PTHrP could be expressed as predominantly amino PTHrP or carboxyl PTHrP in individual lung carcinomas. It also assessed domain-specific effects on cancer progression and patient survival. METHODS: PTHrP immunoreactivities were analyzed versus survival in a human lung cancer tissue microarray (TMA). Growth was compared in athymic mice for isogenic lung carcinoma xenografts differing in expression of amino and carboxyl PTHrP domains. RESULTS: In the TMA, 33 of 99 patient tumors expressed only one PTHrP domain, while 54 expressed both. By Cox regression, the hazard ratio for cancer-specific mortality (95% confidence interval) was 2.6 (1.28-5.44) for amino PTHrP (P = 0.008) and 0.6 (0-2.58) for carboxyl PTHrP (P = 0.092). Xenografts of H358 lung adenocarcinoma cells that overexpressed amino PTHrP grew twice as fast as isogenic low PTHrP tumors in athymic mice, but growth of tumors expressing amino plus carboxyl PTHrP was not significantly different than growth of the control tumors. In summary, the presence of amino PTHrP signifies worse prognosis in lung cancer patients. In mouse xenografts, this effect was abrogated if carboxyl PTHrP was also present. CONCLUSION: Amino PTHrP and carboxyl PTHrP can vary independently in different lung carcinomas. Carboxyl PTHrP may temper the stimulatory effect of amino PTHrP on cancer progression.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteína Relacionada ao Hormônio Paratireóideo/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Animais , Biomarcadores Tumorais/biossíntese , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Domínios Proteicos/genética , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Nihon Shokakibyo Gakkai Zasshi ; 113(9): 1564-71, 2016 09.
Artigo em Japonês | MEDLINE | ID: mdl-27593366

RESUMO

A 76-year-old woman was referred to our hospital with anorexia. Computed tomography revealed a tumor lesion measuring 110mm in the liver at S4/5 with calcification and swelling of a paraaortic lymph node. The gallbladder was not visualized. Histological examination of a biopsy specimen from the liver tumor revealed squamous cell and undifferentiated carcinomas, and several tumor markers were elevated. Therefore, we diagnosed the patient with gallbladder adenosquamous cell carcinoma T3N2M0 stage III. Because the serum parathyroid hormone-related protein (PTHrP) and granulocyte-colony stimulating factor (G-CSF) levels were significantly elevated, we suspected that PTHrP and G-CSF production occurred because of adenosquamous cell carcinoma in the gallbladder. We initiated chemotherapy with S-1.


Assuntos
Carcinoma Adenoescamoso/química , Neoplasias da Vesícula Biliar/química , Neoplasias da Vesícula Biliar/patologia , Fator Estimulador de Colônias de Granulócitos/sangue , Proteína Relacionada ao Hormônio Paratireóideo/sangue , Idoso , Biópsia , Carcinoma Adenoescamoso/diagnóstico por imagem , Evolução Fatal , Feminino , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Fator Estimulador de Colônias de Granulócitos/biossíntese , Humanos , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese
7.
Dev Biol ; 411(1): 72-84, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26794256

RESUMO

Fibroblast growth factor (FGF) signaling is a critical regulator of skeletal development. Fgf9 and Fgf18 are the only FGF ligands with identified functions in embryonic bone growth. Mice lacking Fgf9 or Fgf18 have distinct skeletal phenotypes; however, the extent of overlapping or redundant functions for these ligands and the stage-specific contributions of FGF signaling to chondrogenesis and osteogenesis are not known. To identify separate versus shared roles for FGF9 and FGF18, we generated a combined series of Fgf9 and Fgf18 null alleles. Analysis of embryos lacking alleles of Fgf9 and Fgf18 shows that both encoded ligands function redundantly to control all stages of skeletogenesis; however, they have variable potencies along the proximodistal limb axis, suggesting gradients of activity during formation of the appendicular skeleton. Congenital absence of both Fgf9 and Fgf18 results in a striking osteochondrodysplasia and revealed functions for FGF signaling in early proximal limb chondrogenesis. Additional defects were also noted in craniofacial bones, vertebrae, and ribs. Loss of alleles of Fgf9 and Fgf18 also affect the expression of genes encoding other key intrinsic skeletal regulators, including IHH, PTHLH (PTHrP), and RUNX2, revealing potential direct, indirect, and compensatory mechanisms to coordinate chondrogenesis and osteogenesis.


Assuntos
Desenvolvimento Ósseo/genética , Osso e Ossos/embriologia , Condrogênese/genética , Fator 9 de Crescimento de Fibroblastos/fisiologia , Fatores de Crescimento de Fibroblastos/fisiologia , Osteocondrodisplasias/genética , Osteogênese/genética , Animais , Osso e Ossos/anormalidades , Diferenciação Celular , Condrócitos/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/biossíntese , Fator 9 de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/genética , Lâmina de Crescimento/embriologia , Proteínas Hedgehog/biossíntese , Camundongos , Camundongos Knockout , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Transdução de Sinais/genética
8.
Cell Tissue Res ; 364(2): 299-308, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26662056

RESUMO

In the developing limb, differentiation of skeletal progenitors towards distinct connective tissues of the digits is correlated with the establishment of well-defined domains of Btg1 gene expression. Zones of high expression of Btg1 include the earliest digit blastemas, the condensing mesoderm at the tip of the growing digits, the peritendinous mesenchyme, and the chondrocytes around the developing interphalangeal joints. Gain- and loss-of function experiments in micromass cultures of skeletal progenitors reveal a negative influence of Btg1 in cartilage differentiation accompanied by up-regulation of Ccn1, Scleraxis and PTHrP. Previous studies have assigned a role to these factors in the aggregation of progenitors in the digit tips (Ccn1), in the differentiation of tendon blastemas (Scleraxis) and repressing hypertrophic cartilage differentiation (PTHrP). Overexpression of Btg1 up-regulates the expression of retinoic acid and thyroid hormone receptors, but, different from other systems, the influence of BTG1 in connective tissue differentiation appears to be independent of retinoic acid and thyroid hormone signaling.


Assuntos
Cartilagem/citologia , Condrogênese/fisiologia , Extremidades/embriologia , Mesoderma/metabolismo , Proteínas de Neoplasias/metabolismo , Dedos do Pé/embriologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Embrião de Galinha , Condrócitos/citologia , Condrócitos/metabolismo , Proteína Rica em Cisteína 61/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/biossíntese , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Receptores dos Hormônios Tireóideos/biossíntese , Transdução de Sinais/fisiologia , Tretinoína/metabolismo
9.
BMC Cancer ; 15: 925, 2015 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-26597083

RESUMO

BACKGROUND: Better methods to predict prognosis can play a supplementary role in administering individualized treatment for breast cancer patients. Altered expressions of PTHrP and TGF-ß have been observed in various types of human cancers. The objective of the current study was to evaluate the association of PTHrP and TGF-ß level with the clinicopathological features of the breast cancer patients. METHODS: Immunohistochemistry was used to examine PTHrP and TGF-ß protein expression in 497 cases of early breast cancer, and Kaplan-Meier method and COX's Proportional Hazard Model were applied to the prognostic value of PTHrP and TGF-ß expression. RESULTS: Both over-expressed TGF-ß and PTHrP were correlated with the tumor in larger size, higher proportion of axillary lymph node metastasis and later clinical stage. Additionally, the tumors with a high TGF-ß level developed poor differentiation, and only TGF-ß expression was associated with disease-free survival (DFS) of the breast cancer patients. Followed up for a median of 48 months, it was found that only the patients with negative TGF-ß expression had longer DFS (P < 0.05, log-rank test). Nevertheless, those with higher PTHrP expression tended to show a higher rate of bone metastasis (67.6 % vs. 45.8 %, P = 0.019). In ER negative subgroup, those who developed PTHrP positive expression presented poor prognosis (P < 0.05, log-rank test). The patients with both positive TGF-ß and PTHrP expression were significantly associated with the high risk of metastases. As indicated by Cox's regression analysis, TGF-ß expression and the high proportion of axillary lymph node metastasis served as significant independent predictors for breast cancer recurrence. CONCLUSIONS: TGF-ß and PTHrP were confirmed to be involved in regulating the malignant progression in breast cancer, and PTHrP expression, to be associated with bone metastasis as a potential prognostic marker in ER negative breast cancer.


Assuntos
Neoplasias da Mama/genética , Recidiva Local de Neoplasia/genética , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Fator de Crescimento Transformador beta/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Proteína Relacionada ao Hormônio Paratireóideo/genética , Prognóstico , Fator de Crescimento Transformador beta/genética
10.
PLoS One ; 10(4): e0122764, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25859665

RESUMO

Breast cancer is the major cause of cancer death in women worldwide. The most common site of metastasis is bone. Bone metastases obstruct the normal bone remodeling process and aberrantly enhance osteoclast-mediated bone resorption, which results in osteolytic lesions. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is an endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARγ) that has anti-inflammatory and antitumor activity at micromolar concentrations through PPARγ-dependent and/or PPARγ-independent pathways. We investigated the inhibitory activity of 15d-PGJ2 on the bone loss that is associated with breast cancer bone metastasis and estrogen deficiency caused by cancer treatment. 15d-PGJ2 dose-dependently inhibited viability, migration, invasion, and parathyroid hormone-related protein (PTHrP) production in MDA-MB-231 breast cancer cells. 15d-PGJ2 suppressed receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA levels and normalized osteoprotegerin (OPG) mRNA levels in hFOB1.19 osteoblastic cells treated with culture medium from MDA-MB-231 cells or PTHrP, which decreased the RANKL/OPG ratio. 15d-PGJ2 blocked RANKL-induced osteoclastogenesis and inhibited the formation of resorption pits by decreasing the activities of cathepsin K and matrix metalloproteinases, which are secreted by mature osteoclasts. 15d-PGJ2 exerted its effects on breast cancer and bone cells via PPARγ-independent pathways. In Balb/c nu/nu mice that received an intracardiac injection of MDA-MB-231 cells, subcutaneously injected 15d-PGJ2 substantially decreased metastatic progression, cancer cell-mediated bone destruction in femora, tibiae, and mandibles, and serum PTHrP levels. 15d-PGJ2 prevented the destruction of femoral trabecular structures in estrogen-deprived ICR mice as measured by bone morphometric parameters and serum biochemical data. Therefore, 15d-PGJ2 may be beneficial for the prevention and treatment of breast cancer-associated bone diseases.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Reabsorção Óssea/metabolismo , Neoplasias da Mama/patologia , Estrogênios/deficiência , Prostaglandina D2/análogos & derivados , Anilidas/farmacologia , Animais , Neoplasias Ósseas/tratamento farmacológico , Reabsorção Óssea/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Osteoclastos/metabolismo , Osteólise/tratamento farmacológico , Osteólise/metabolismo , Osteoprotegerina/metabolismo , Ovariectomia , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Prostaglandina D2/farmacologia , Ligante RANK/metabolismo
11.
J Cancer Res Clin Oncol ; 141(11): 1931-43, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25820528

RESUMO

BACKGROUND: An increasingly high occurrence of bone metastases in hepatocellular carcinoma (HCC) patients highlights the importance of fundamental research on HCC bone metastasis, which has been limited in its success due to the lack of a model system. PURPOSE: Establishment of animal and cellular models of HCC bone metastasis and discovery of HCC bone metastasis-related genes. METHODS: Luciferase-transfected HCC cell lines HCCLM3, MHCC97H, and SMMC-7721 were used to inoculate nude mice intracardially. Formation of bone metastases was examined by bioluminescence imaging, SPECT, and pathology study. Metastatic cells in bone were isolated and subcultured. Differences between bone metastatic cells and their parental cells were studied by in vitro/in vivo assays. RESULTS: Mouse model of HCC bone metastasis was successfully established. Injected tumour cells formed metastases in the skull, the spine, the hind limbs, and the sternum, causing osteolytic lesions via act of MMP-1 and recruitment of osteoclasts. Four bone metastatic cell lines were extracted from HCCLM3-inoculated mice and were demonstrated to exhibit a much stronger ability to form bone metastases as well as other phenotypes, including enhanced in vitro migration/invasion and colony formation. Moreover, the expression of PTHrP, MMP-1, and CTGF was significantly elevated in bone metastatic cells compared to parental HCC cells. CONCLUSION: The nude mouse model and bone metastatic cell lines together provide an effective simulation of HCC bone metastasis. This model system will become powerful tool with which to explore the mechanisms and therapies of HCC bone metastasis. Additionally, PTHrP, MMP-1, and CTGF are candidate genes related to HCC bone metastasis.


Assuntos
Neoplasias Ósseas/secundário , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Neoplasias Experimentais/patologia , Animais , Neoplasias Ósseas/genética , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Fator de Crescimento do Tecido Conjuntivo/biossíntese , Neoplasias Hepáticas/genética , Luciferases , Substâncias Luminescentes , Medições Luminescentes , Metaloproteinase 13 da Matriz/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais/genética , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Tomografia Computadorizada de Emissão de Fóton Único
12.
Kyobu Geka ; 68(3): 237-9, 2015 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-25743561

RESUMO

An 82-year-old man was admitted to our hospital with hemoptysis and weight loss. Chest computed tomography(CT) showed a 90 mm mass with cavity formation in the right lower lobe adjacent to chest wall. Laboratory data revealed hypercalcemia and elevation of parathyroid hormone-related protein C (PTHrP). He was diagnosed as squamous cell carcinoma of lung by transbronchial lung biopsy (TBLB) [cT3aN1M0]. Nausea and anorexia due to hypercalcemia became worse and a right middle and lower lobectomy was performed because of difficult control of symptoms by medicine and worsening of his general condition. His symptoms were improved immediately after surgery.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirurgia , Hipercalcemia/etiologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgia , Síndromes Paraneoplásicas/etiologia , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Masculino , Pneumonectomia , Resultado do Tratamento
13.
Nihon Shokakibyo Gakkai Zasshi ; 111(11): 2163-73, 2014 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-25373378

RESUMO

An 87-year-old woman was diagnosed with primary diffuse large B-cell lymphoma of the pancreas by endoscopic ultrasonography-guided fine needle aspiration. Complete remission was achieved after treatment with six courses of R-CHOP chemotherapy. However, two and a half years later, she was readmitted because of weakness during walking. At this time, laboratory tests revealed hypercalcemia associated with high plasma levels of parathyroid hormone-related protein (PTHrP), but bone lesions were not detected. Although computed tomography only revealed splenomegaly, we suspected a recurrence of her malignant lymphoma because she also had marked elevation of soluble interleukin-2 receptor and lactate dehydrogenase levels. Bone marrow examination revealed the involvement of Burkitt's lymphoma cells with malignant transformation. Immunohistochemical analysis confirmed that hypercalcemia was caused by a paraneoplastic syndrome related to PTHrP-producing B-cell lymphoma cells. Unfortunately, the patient's general condition rapidly deteriorated, and she died soon after admission. Our case is unusual because of the presentation of bone marrow relapse of malignant lymphoma.


Assuntos
Hipercalcemia/etiologia , Linfoma de Células B/complicações , Neoplasias Pancreáticas/complicações , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Idoso de 80 Anos ou mais , Biópsia , Feminino , Humanos , Linfoma de Células B/metabolismo , Neoplasias Pancreáticas/metabolismo , Recidiva
14.
Clin Calcium ; 24(6): 863-9, 2014 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-24870837

RESUMO

PTH-related peptide (PTHrP) is a widely distributed cytokine, which shares the cognate receptor PTHR1 with PTH. Originally identified as a causal factor of humoral hypercalcemia of malignancy twenty years ago, PTHrP is now recognized as a critical physiological regulator of various biological processes, including bone and cartilage metabolism.


Assuntos
Osso e Ossos/metabolismo , Cartilagem/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/fisiologia , Animais , Neoplasias Ósseas/secundário , Humanos , Hipercalcemia/etiologia , Camundongos , Neoplasias/complicações , Neoplasias/metabolismo , Osteoporose/tratamento farmacológico , Síndromes Paraneoplásicas/etiologia , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Receptor Tipo 1 de Hormônio Paratireóideo/fisiologia
15.
PLoS One ; 9(5): e90418, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24785493

RESUMO

Parathyroid hormone-related protein (PTHrP) can be secreted from cells and interact with its receptor, the Type 1 PTH/PTHrP Receptor (PTHR1) in an autocrine, paracrine or endocrine fashion. PTHrP can also remain inside cells and be transported into the nucleus, where its functions are unclear, although recent experiments suggest that it may broadly regulate cell survival and senescence. Disruption of either the PTHrP or PTHR1 gene results in many abnormalities including a failure of embryonic mammary gland development in mice and in humans. In order to examine the potential functions of nuclear PTHrP in the breast, we examined mammary gland development in PTHrP (1-84) knock-in mice, which express a mutant form of PTHrP that lacks the C-terminus and nuclear localization signals and which can be secreted but cannot enter the nucleus. Interestingly, we found that PTHrP (1-84) knock-in mice had defects in mammary mesenchyme differentiation and mammary duct outgrowth that were nearly identical to those previously described in PTHrP-/- and PTHR1-/- mice. However, the mammary buds in PTHrP (1-84) knock-in mice had severe reductions in mutant PTHrP mRNA levels, suggesting that the developmental defects were due to insufficient production of PTHrP by mammary epithelial cells and not loss of PTHrP nuclear function. Examination of the effects of nuclear PTHrP in the mammary gland in vivo will require the development of alternative animal models.


Assuntos
Deleção de Genes , Glândulas Mamárias Animais/embriologia , Glândulas Mamárias Animais/metabolismo , Sinais de Localização Nuclear/genética , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Proteína Relacionada ao Hormônio Paratireóideo/genética , Domínios e Motivos de Interação entre Proteínas , Animais , Biomarcadores/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos , Camundongos Transgênicos , Proteína Relacionada ao Hormônio Paratireóideo/química , Fragmentos de Peptídeos/genética , Caracteres Sexuais
16.
Invest New Drugs ; 32(1): 1-13, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23673814

RESUMO

Breast cancer frequently spreads to bone. The interaction between bone metastases and microenvironment, referred as the "vicious cycle", increases both tumor burden and bone destruction. Therefore, inhibition at any point in this "vicious cycle" can reduce malignant osteolytic lesions in patients with advanced breast cancer. In this study, we evaluated whether tetrahydrofurofuran-type lignans derived from Magnoliae Flos, commonly used in traditional Asian medicine to treat inflammatory diseases, could block breast cancer-mediated bone loss. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin at noncytotoxic concentrations suppressed mRNA expression and secretion of osteolytic factor PTHrP in MDA-MB-231 metastatic human breast cancer cells. Fargesin inhibited TGF-ß-stimulated cell viability, migration, and invasion and decreased TGF-ß-induced PTHrP production in MDA-MB-231 cells. In addition, these lignans reduced RANKL/OPG ratio in PTHrP-treated hFOB1.19 human osteoblastic cells and inhibited RANKL-mediated osteoclast differentiation in mouse bone marrow macrophages. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin substantially reduced bone-resorbing activity of osteoclasts by inhibiting MMP-9 and cathepsin K activities. Furthermore, orally administered fargesin inhibited tumor growth and cancer-mediated bone destruction in mice with MDA-MB-231 cells injected into calvarial tissues. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin blocked initiation and progression of the "vicious cycle" between breast cancer metastases and bone microenvironment by inhibiting PTHrP production in breast cancer cells and osteoclastic bone resorption. Therefore, these tetrahydrofurofuran-type lignans have the potential to serve as beneficial agents to prevent and treat cancer-induced bone destruction in breast cancer patients.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Neoplasias da Mama/patologia , Furanos/uso terapêutico , Lignina/uso terapêutico , Osteoblastos/patologia , Osteoclastos/patologia , Animais , Benzodioxóis/química , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Furanos/química , Furanos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lignanas/química , Lignanas/farmacologia , Lignanas/uso terapêutico , Lignina/química , Lignina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Ligante RANK/genética , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
Oncol Rep ; 31(1): 3-12, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24253735

RESUMO

Susceptibly to the induction of rat tongue cancer (TC) by oral 4-nitroquinoline 1-oxide (4NQO) exposure is a polygenic trait. Among several quantitative trait loci identified by crosses between TC-susceptible Dark Agouti (DA) rats and TC-resistant Wistar-Furth (WF) rats, we focused on tongue cancer susceptibility locus (Tcas3) of chromosome 4. We examined tongue carcinogenesis in the reciprocal congenic strains DA.WF-Tcas3 and WF.DA-Tcas3 and in their parental strains. The Tcas3DA allele, and not the Tcas3WF allele, significantly favored tumor latency, incidence and TC number/size. In genomic DNA of TCs induced in (DA x WF) F1 rats, the resistant Tcas3WF allele was frequently and selectively lost, particularly in larger tumors. Thus, we searched the possible candidate genes in the Tcas3 region using microarray analysis of TCs in F1 rats and revealed significant upregulation of 2 cancer-related genes, parathyroid hormone-like hormone (Pthlh) and Kras2. The relevance of the WF allele of Pthlh as a cancer modifier was indicated by 3 single nucleotide polymorphisms specific to this strain. In contrast, no consistent strain-specific variations were found in Kras2. Moreover, the plasma Ca2+ level was consistently higher in DA rats when compared to the level in WF rats bearing TCs; moreover, the Pthlh-mRNA expression level was >30-fold higher in TCs when compared to this level in the normal tongue mucosa. Immunostaining experiments showed strong PTHrP protein expression in TCs of DA rats, and the signal was intensified in larger TCs. Kras2 was also upregulated in TCs, but to a lesser degree than PTHrP. Thus, Pthlh is a promising candidate modifier gene in the development and progression of rat TCs.


Assuntos
4-Nitroquinolina-1-Óxido/toxicidade , Carcinógenos/toxicidade , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Proteína Relacionada ao Hormônio Paratireóideo/genética , Neoplasias da Língua/induzido quimicamente , Neoplasias da Língua/genética , Animais , Sequência de Bases , Predisposição Genética para Doença , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas p21(ras)/biossíntese , Proteínas Proto-Oncogênicas p21(ras)/genética , Locos de Características Quantitativas/genética , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos WF , Ratos Long-Evans , Ratos Sprague-Dawley , Análise de Sequência de DNA
18.
Surg Today ; 44(8): 1577-83, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24013836

RESUMO

Combined hepatocellular-cholangiocarcinoma (CHCC) is an uncommon form of primary liver cancer. A 57-year-old man was readmitted to our hospital for treatment of recurrent CHCC, 12 months after central bisegmentectomy and 4 months after limited hepatic resection. Magnetic resonance imaging (MRI) revealed multiple hepatic nodules. Laboratory data showed increased serum levels of α-fetoprotein (AFP), calcium, and parathyroid hormone-related protein (PTH-rP), to 5,571 ng/mL, 17.0 mg/dL, and 16.1 pmol/L, respectively. Palliative mass reduction surgery was indicated by the fact that the hypercalcemia was difficult to manage medically. Thus, we performed lateral segmentectomy with partial resection of segment 7 and the caudate lobe, and microwave coagulation therapy for multiple recurrent CHCC. Thereafter, the serum PTH-rP and AFP levels decreased remarkably and the hypercalcemia was controlled for the next 3 months. He died of disease progression 9 months after the last hepatic surgery. To our knowledge, this is only the second reported case of CHCC producing PTH-rP in the English-language literature.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirurgia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/cirurgia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Neoplasias Primárias Múltiplas , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Cálcio/sangue , Carcinoma Hepatocelular/diagnóstico , Colangiocarcinoma/diagnóstico , Evolução Fatal , Hepatectomia/métodos , Humanos , Neoplasias Hepáticas/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Cuidados Paliativos , Proteína Relacionada ao Hormônio Paratireóideo/sangue , alfa-Fetoproteínas/análise
19.
J Bone Miner Res ; 29(1): 55-66, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23787729

RESUMO

To promote their survival and progression in the skeleton, osteotropic malignancies of breast, lung, and prostate produce parathyroid hormone-related protein (PTHrP), which induces hypercalcemia. PTHrP serum elevations have also been described in multiple myeloma (MM), although their role is not well defined. When we investigated MM cells from patients and cell lines, we found that PTHrP and its receptor (PTH-R1) are highly expressed, and that PTHrP is secreted both as a full-length molecule and as small subunits. Among these subunits, the mid-region, including the nuclear localization sequence (NLS), exerted a proliferative effect because it was accumulated in nuclei of MM cells surviving in starvation conditions. This was confirmed by increased transcription of several genes enrolled in proliferation and apoptosis control. PTHrP was also found to stimulate PTH-R1 in MM cells. PTH-R1's selective activation by the full-length PTHrP molecule or the NH2 -terminal fragment resulted in a significant increase of intracellular Ca(2+) influx, cyclic adenosine monophosphate (cAMP) content, and expression of receptor activator of NF-κB ligand (RANKL) and monocyte chemoattractant protein-1 (MCP-1). Our data definitely clarify the role of PTHrP in MM. The PTHrP peptide is functionally secreted by malignant plasma cells and contributes to MM tumor biology and progression, both by intracrine maintenance of cell proliferation in stress conditions and by autocrine or paracrine stimulation of PTH-R1, which in turn reinforces the production of osteoclastogenic factors. © 2014 American Society for Bone and Mineral Research.


Assuntos
Mieloma Múltiplo/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Plasmócitos/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/biossíntese , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CCL2/biossíntese , AMP Cíclico/metabolismo , Progressão da Doença , Humanos , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/farmacologia , Receptor Ativador de Fator Nuclear kappa-B/biossíntese , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo
20.
Genet Mol Res ; 12(3): 3363-74, 2013 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-24065677

RESUMO

Parathyroid hormone-related protein (PTHrP) is a protein member of the parathyroid hormone family that regulates the dynamic balance between blood and bone calcium during lactation. However, the mechanism of its regulation is not very clear. In order to establish a framework for further functional studies of the PTHrP gene in goat mammary gland epithelial cells during the lactation period, PTHrP cDNA was isolated from Xinong Saanen dairy goats. Its coding sequence is 534 bp in size. We also designed a short hairpin RNA (shRNA) to efficiently inhibit PTHrP expression and constructed recombinant adenoviruses carrying a template encoding this shRNA (AD-PTHrP-322) using the Block-iT shRNA interference system. Finally, the inhibition of PTHrP expression by the recombinant adenoviruses was confirmed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blotting. qRT-PCR results showed that the expression of PTHrP mRNA in mammary epithelial cells was downregulated by 29.2, 68.1, and 82.6% 24, 48, and 72 h after the cells were infected with AD-PTHrP-322, respectively. Western blotting also showed that the expression of PTHrP was reduced in a time-dependent manner. These results suggest that AD-PTHrP-322 significantly inhibits the expression of PTHrP.


Assuntos
Adenoviridae/genética , Regulação da Expressão Gênica/genética , Proteína Relacionada ao Hormônio Paratireóideo/genética , RNA Interferente Pequeno/genética , Animais , Células Epiteliais/metabolismo , Feminino , Vetores Genéticos , Cabras/genética , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/antagonistas & inibidores , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese
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