Autocrine and paracrine STIP1 signaling promote osteolytic bone metastasis in renal cell carcinoma

Wang, Jiang; You, Hongbo; Qi, Jun; Yang, Chen; Ren, Ye; Cheng, Hao

doi:10.18632/oncotarget.15222

Cited by 30 publications

(21 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2a, b). Our previous results indicated that rhHOP promoted hepatocellular carcinoma cell (HCC) proliferation [25], and it was reported that rhHOP increased ovarian cancer cell viability [24] and renal cell cancer metastasis [26]. Thus, we determined the effects of HOP on GC cell growth.…”

Section: Exogenous Hop Signaling Promoted Cell Proliferation In Gc Cementioning

confidence: 96%

HSP70/HSP90-Organizing Protein Contributes to Gastric Cancer Progression in an Autocrine Fashion and Predicts Poor Survival in Gastric Cancer

Zhai

Liang

Lin³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: HSP70/HSP90-organizing protein (HOP) is an adaptor protein that mediates heat shock protein 70 (HSP70) and HSP90 folding. HOP can be secreted by cancer cells and promote malignant cell growth in an autocrine manner. Here, we studied its role in gastric cancer (GC). Methods: HOP mRNA and protein levels were detected by quantitative real-time PCR and western blotting, respectively, and enzyme-linked immunosorbent assay was used to determine the serum levels. Immunohistochemistry was performed to analyze HOP expression in 117 GC tissues and 32 adjacent normal tissues. The Cell Counting Kit-8 cell viability assay, flow cytometry, and western blotting were used to analyze the effects of HOP on cell proliferation and apoptosis, and the potential underlying mechanisms. Results: HOP mRNA and protein levels were significantly higher in GC tissues than in normal tissues in our medical center (P< 0.001) and in The Cancer Genome Atlas database (P< 0.001). GC patients had higher serum levels of HOP than age-matched healthy controls (P< 0.001); however, once tumors were removed, serum levels significantly decreased (P< 0.01). In human GC tissues, increased HOP expression was associated with tumor progression and poor survival. Notably, autocrine HOP promoted cell proliferation through the phospholipase Cγ1-extracellular signal-regulated kinase 1/2-dependent pathway, and inhibited cell apoptosis by regulating the activities of caspase 9, caspase 3, and B-cell lymphoma 2. Blocking extracellular HOP with neutralizing antibody reduced proliferation and enhanced fluorouracil-induced apoptosis of GC cells. Conclusions: Our findings demonstrate that HOP is an important molecular marker and prognostic factor for GC, and functionally contributes to tumor cell growth and survival. These results provide a rationale for considering HOP as a potential therapeutic target and chemosensitizer in GC.

show abstract

Section: Exogenous Hop Signaling Promoted Cell Proliferation In Gc Cementioning

confidence: 96%

HSP70/HSP90-Organizing Protein Contributes to Gastric Cancer Progression in an Autocrine Fashion and Predicts Poor Survival in Gastric Cancer

Zhai

Liang

Lin³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Knockout mice lacking STIP1 are embryonic lethal, suggesting a key developmental role for this molecule 6 . Growing evidence also indicates that STIP1 is markedly overexpressed in various human solid malignancies 7 – 13 . Conversely, its repression blocks both tumor cell proliferation 11 and migration 14 .…”

Section: Introductionmentioning

confidence: 99%

Stress-induced phosphoprotein 1 acts as a scaffold protein for glycogen synthase kinase-3 beta-mediated phosphorylation of lysine-specific demethylase 1

et al. 2018

View full text Add to dashboard Cite

Stress-induced phosphoprotein 1 (STIP1)—a co-chaperone of heat shock proteins—promotes cell proliferation and may act as an oncogenic factor. Similarly, glycogen synthase kinase-3 beta (GSK3β)-mediated phosphorylation of lysine-specific demethylase 1 (LSD1)—an epigenetic regulator—can contribute to the development of an aggressive cell phenotype. Owing to their ability to tether different molecules into functional complexes, scaffold proteins have a key role in the regulation of different signaling pathways in tumorigenesis. Here, we show that STIP1 acts as a scaffold promoting the interaction between LSD1 and GSK3β. Specifically, the TPR1 and TPR2B domains of STIP1 are capable of binding with the AOL domain of LSD1, whereas the TPR2A and TPR2B domains of STIP1 interact with the kinase domain of GSK3β. We also demonstrate that STIP1 is required for GSK3β-mediated LSD1 phosphorylation, which promoted LSD1 stability and enhanced cell proliferation. After transfection of cancer cells with double-mutant (S707A/S711A) LSD1, subcellular localization analysis revealed that LSD1 was translocated from the nucleus to the cytoplasm. In vitro experiments also showed that the LSD1 inhibitor SP2509 and the GSK3β inhibitor LY2090314 acted synergistically to induce cancer cell death. Finally, the immunohistochemical expression of STIP1 and LSD1 showed a positively correlation in human cancer specimens. In summary, our data provide mechanistic insights into the role of STIP1 in human tumorigenesis by showing that it serves as a scaffold for GSK3β-mediated LSD1 phosphorylation. The combination of LSD1 and GSK3β inhibitors may exert synergistic antitumor effects and deserves further scrutiny in preclinical studies.

show abstract

“…Moreover, patients with metastatic RCC (mRCC) of other organs represent an unfavorable subset of individuals. Especially the occurrence of the bone metastasis is widely accepted as a significant prognostic factor of life expectancy of patients [3] .…”

Section: Introductionmentioning

confidence: 99%

Risk factors for bone metastasis from renal cell cancer

Chen

Lan

Zhou

et al. 2017

Journal of Bone Oncology

View full text Add to dashboard Cite

ObjectiveThe prognosis for renal cell carcinoma (RCC) is related to a high rate of metastasis, including 30% of bone metastasis. In this study, we investigate the correlation between diverse clinical factors and bone metastases secondary from renal cell cancer (RCC), and to identify potential risk factors for bone metastasis in newly diagnosed patients and those who have already received treatment.MethodsThe clinical data of 372 patients with RCC were reviewed from January 2000 to August 2016. The correlations between age, gender, histopathologic types, alkaline phosphotase (ALP), CEA, AFP, CA-125, CA-153, CA-199, calcium, hemoglobin (HB) and bone metastases were analyzed. And the risk factors for bone metastases in RCC were identified by multivariate logistic regression analysis. The cutoff value, sensitivity and specificity of the independent correlation factors were calculated by receiver operating characteristic (ROC) curve.ResultsThe bone is the second to the lung as a distant metastasis target site in patients with RCC. Thirty eight individuals were identified with bone metastases. Of these patients, significantly higher levels of ALP, calcium, HB were found than those without bone metastasis (P < 0.05, respectively). No significant differences were detected in CEA, AFP, CA-125, CA-153, CA-199, age, gender and histopathologic types between patients with and without bone metastases (P > 0.05, respectively). Multivariate logistic regression analysis indicated that ALP, calcium and HB were independent risk factors correlated with bone metastasis (P < 0.05, respectively). ROC curves demonstrated these factors had comparable accuracy at predicting bone metastasis (AUC were 0.749, 0.633 and 0.665, respectively). The cutoff values of ALP, calcium and HB were 105.5 U/L, 2.615 mmol/L and 111.5 g/L, respectively. The sensitivities of them were 57.9%, 36.8% and 71.1% for predicting bone metastasis, with specificities of 83.5%, 95.2% and 65.3%, respectively.ConclusionBased on our study, the concentrations of ALP, calcium and HB were potentially risk factors for bone metastasis in patients with RCC. For newly diagnosed patients, if the values of ALP>105.5 U/L, calcium>2.615 mmol/L and HB<111.5 g/L were detected, intensive monitoring and bone scanning are warranted for them.

show abstract

Autocrine and paracrine STIP1 signaling promote osteolytic bone metastasis in renal cell carcinoma

Cited by 30 publications

References 43 publications

HSP70/HSP90-Organizing Protein Contributes to Gastric Cancer Progression in an Autocrine Fashion and Predicts Poor Survival in Gastric Cancer

HSP70/HSP90-Organizing Protein Contributes to Gastric Cancer Progression in an Autocrine Fashion and Predicts Poor Survival in Gastric Cancer

Stress-induced phosphoprotein 1 acts as a scaffold protein for glycogen synthase kinase-3 beta-mediated phosphorylation of lysine-specific demethylase 1

Risk factors for bone metastasis from renal cell cancer

Contact Info

Product

Resources

About