Blocking stanniocalcin 2 reduces sunitinib resistance in clear cell renal cell carcinoma

Qin, Zhenqian; Li, Kongdong; Chu, Hezhen; Yuan, Xuefeng; Shi, Haifeng; Gu, Jie; Xie, Yimin

doi:10.4149/neo_2021_210823n1206

Cited by 3 publications

(8 citation statements)

References 30 publications

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“…In our previous study, the sunitinib resistance of ccRCC cells in normoxia condition had been detected 30 . In the present study, we aimed to identify the efficacy of sunitinib on Caki-1 cells and the underlying mechanism under hypoxia conditions.…”

Section: Resultsmentioning

confidence: 95%

“…Both in vivo and in vitro results indicated that STC1 mediated gemcitabine resistance in pancreatic ductal adenocarcinoma 39 . Our previous study showed that sunitinib treatments reduced the expression of STC2 both mRNA and protein levels, which could reduce sunitinib resistance of Caki-1 cells 30 . All these studies detected the roles of STCs in drug resistance under normoxia but not hypoxia, and the latter one is a real pathophysiological environment of tumors and important for the cancer incidence and development.…”

Section: Discussionmentioning

confidence: 94%

“…Studies have shown that resistance to sunitinib in ccRCC is attributed to lysosomal sequestration and inhibition of autophagy flux 11 , 12 . Our previous study reported that sunitinib accumulated in the cells and destroyed the lysosome pH 30 . However, STC2-neutralizing antibodies suppressed sunitinib accumulation was independent of restoring the lysosome pH 30 .…”

Section: Discussionmentioning

confidence: 97%

“…It found that high expression of STC2 was associated with tumor invasiveness and shortened overall survival in patients with RCC 28 , 29 . Our previous study showed that blocking STC2 could reduce sunitinib resistance in ccRCC cells 30 . However, the effect of STC2 in ccRCC under hypoxia and its molecular mechanism is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Inhibiting stanniocalcin 2 reduces sunitinib resistance of Caki-1 renal cancer cells under hypoxia condition

Chu,

Xie,

Guo

et al. 2023

Annals of Medicine &Amp; Surgery

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Background: Our previous study has suggested that blocking stanniocalcin 2 (STC2) could reduce sunitinib resistance in clear cell renal cell carcinoma (ccRCC) under normoxia. The hypoxia is a particularly important environment for RCC occurrence and development, as well as sunitinib resistance. We proposed that STC2 also plays important roles in RCC sunitinib resistance under hypoxia conditions. Methods: The ccRCC Caki-1 cells were treated within the hypoxia conditions. Real-time quantitative PCR and Western blotting were applied to detect the STC2 expression in ccRCC Caki-1 cells. STC2-neutralizing antibodies, STC2 siRNA, and the recombinant human STC2 (rhSTC2) were used to identify targeting regulation on STC2 in modulating sunitinib resistance, proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion. In addition, autophagy flux and the lysosomal acidic environment were investigated by Western blotting and fluorescence staining, and the accumulation of sunitinib in cells was observed with the addition of STC2-neutralizing antibodies and autophagy modulators. Results: Under hypoxia conditions, sunitinib disrupted the lysosomal acidic environment and accumulated in Caki-1 cells. Hypoxia induced the STC2 mRNA and protein levels in Caki-1 cells. STC2-neutralizing antibodies and STC2 siRNA effectively aggravated sunitinib-reduced cell viability and proliferation, which were reversed by rhSTC2. In addition, sunitinib promoted EMT, migration, and invasion, which were reduced by STC2-neutralizing antibodies. Conclusion: Inhibiting STC2 could reduce sunitinib resistance of ccRCC cells under hypoxia conditions.

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Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Inhibiting stanniocalcin 2 reduces sunitinib resistance of Caki-1 renal cancer cells under hypoxia condition

Chu,

Xie,

Guo

et al. 2023

Annals of Medicine &Amp; Surgery

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“…On the other hand, several studies showed that STC2 is a protective factor for some tumors. STC2 reduces resistance to sunitinib in clear-cell renal cell carcinoma (Qin et al, 2022). STC2 inhibits migration and invasion of breast cancer via inhibition of PKC signaling (Hou et al, 1932).…”

Section: Introductionmentioning

confidence: 99%

A Pan-Cancer Analysis Reveals the Prognostic and Immunotherapeutic Value of Stanniocalcin-2 (STC2)

et al. 2022

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Background: Stanniocalcin-2 (STC2) is a secreted glycoprotein which plays an important role in regulating the homeostasis of calcium, glucose homeostasis, and phosphorus metastasis. Accumulating evidence suggests that STC2 is implicated in cancer mechanisms. However, the effects of STC2 on cancer development and progression across pan-cancer are not yet completely known.Methods: Data were downloaded from The Cancer Genome Atlas database to obtain differentially expressed genes significantly associated with prognosis (key genes). A gene was selected for subsequent correlation studies by integrating the significance of prognosis and the time-dependent ROC curve. Gene expression of different tumor types was analyzed based on the UCSC XENA website. Furthermore, our study investigated the correlation of STC2 expression between prognosis, immune cell infiltration, immune checkpoint genes (ICGs), mismatch repair genes (MMRs), tumor mutation burden (TMB), microsatellite instability (MSI), and drug sensitivity in various malignant tumors. Gene set enrichment analysis (GSEA) was conducted for correlated genes of STC2 to explore potential mechanisms.Results: A total of 3,429 differentially expressed genes and 397 prognosis-related genes were identified from the TCGA database. Twenty-six key genes were found by crossing the former and the latter, and the highest risk gene, STC2, was selected for subsequent correlation studies. STC2 had good diagnostic performance for HNSCC, and was closely related to the survival status and clinicopathological stage of HNSCC patients. In pan-cancer analysis, STC2 was upregulated in 20 cancers and downregulated in seven cancers. STC2 overexpression was overall negatively correlated with overall survival, disease-free survival, disease-specific survival, and progress-free survival. STC2 was profoundly correlated with the tumor immune microenvironment, including immune cell infiltration, ICGs, MMRs, TMB, and MSI. Moreover, STC2 was significantly negatively correlated with the sensitivity or resistance of multiple drugs.Conclusion: STC2 was a potential prognostic biomarker for pan-cancer and a new immunotherapy target.

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Stanniocalcin-2 expression in glioblastoma – A novel prognostic biomarker: An observational study

Aydin,

Yildirim

2024

Medicine

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The objective of this study was to assess the prognostic relevance of Stanniocalcin-2 (STC2) expression, as determined via immunohistochemistry in tumor tissue, in a cohort of 83 patients diagnosed with glioblastoma who underwent maximal safe surgical resection followed by radiotherapy concurrent with adjuvant temozolomide. STC2 expression levels were categorized using a 3-tiered semiquantitative system: negative expression (level 0−), low expression (level 1+), and high expression (levels 2 + and 3+). Patients were categorized into 2 distinct groups according to their STC2 expression levels: negative STC2 (−/+) and positive STC2 (++/+++). The primary outcome measure was the relationship between STC2 expression and progression-free survival (PFS), with overall survival (OS) serving as the secondary endpoint. Kaplan–Meier survival analysis confirmed that patients exhibiting high STC2 expression had significantly shorter OS (8 vs 20 months, P < .001) and PFS (6 vs 18 months, P < .001) than those with low or negative STC2 expression. Multivariate analysis revealed that STC2 expression was an independent prognostic factor for both OS (hazard ratio: 0.4; 95% confidence interval: 0.2–0.8; P < .05) and PFS (hazard ratio: 0.3; 95% confidence interval: 0.2–0.4; P < .05) in patients with glioblastoma. Furthermore, elevated STC2 expression in GBM was correlated with several established aggressive clinicopathological characteristics, including advanced age (≥65 years), low ECOG PS (≥2), and isocitrate dehydrogenase mutation negativity. These findings underscore that heightened STC2 expression within the tumor tissue of GBM patients functions as an adverse prognostic marker, correlating with an elevated risk of progression and reduced OS. Therapeutic interventions targeting the AKT-mTOR, ERK1-2, and mitogen-activated protein kinase pathways as well as immune checkpoint inhibitors and vascular endothelial growth factor blockade, as well as potential forthcoming antibody–drug conjugates targeting the STC2 molecule, have the potential to broaden the scope of combined treatment strategies.

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Blocking stanniocalcin 2 reduces sunitinib resistance in clear cell renal cell carcinoma

Cited by 3 publications

References 30 publications

Inhibiting stanniocalcin 2 reduces sunitinib resistance of Caki-1 renal cancer cells under hypoxia condition

Inhibiting stanniocalcin 2 reduces sunitinib resistance of Caki-1 renal cancer cells under hypoxia condition

A Pan-Cancer Analysis Reveals the Prognostic and Immunotherapeutic Value of Stanniocalcin-2 (STC2)

Stanniocalcin-2 expression in glioblastoma – A novel prognostic biomarker: An observational study

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