The Association Between HSP90/topoisomerase I Immunophenotype and the Clinical Features of Colorectal Cancers in Respect to KRAS Gene Status

Bär, Julia; Lis-Nawara, Anna; Grelewski, Piotr; Noga, Leszek; Grzebieniak, Zygmunt; Jeleń, Michał

doi:10.21873/anticanres.11905

Cited by 3 publications

(2 citation statements)

References 22 publications

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“…Notably, mutated RAS may predict sensitivity to HSP90 inhibition due to serine threonine kinase 33-dependent mechanisms in CRC cell lines 14 . According to the tumor tiuuse of CRC, another clinical study has confirmed that a positive correlation exists between KRAS mutation and HSP90 expression 15 . These studies echo the findings of our study.…”

Section: Discussionmentioning

confidence: 97%

Diagnostic, clinicopathologic, therapeutic and prognostic value of Plasma Heat Shock Protein 90 levels in patients with advanced Gastrointestinal Carcinoma

Zhang¹,

Ni²,

Li³

et al. 2020

J. Cancer

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Purpose: Heat shock protein 90 (HSP90) is a critical molecular chaperone for protein folding, intracellular disposition and regulation of tumor biological behavior in the extracellular space. HSP90 has received much attention due to its specific effect in gastrointestinal cancer. This clinical study sought to determine whether HSP90 in plasma may serve as a biomarker in patients with advanced gastrointestinal carcinoma. Methods: Using human plasma samples of advanced gastrointestinal carcinoma, we investigated the specific value of HSP90 in gastrointestinal cancer from a clinical perspective. Results: In summary, plasma levels of HSP90 were shown to be higher in patients with gastric cancer (GC) or colorectal cancer (CRC) than in controls with benign gastrointestinal diseases. In both GC and CRC patients, HSP90 was significantly associated with live metastasis. Higher HSP90 levels were more frequent in CRC patients with hazardous or harmful alcohol consumption habits. Patients with RAS mutations had higher HSP90 levels in CRC. Compared with Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 19-9 (CA19-9), HSP90 benefited patients by enhancing diagnostic sensitivity and the Youden index. The levels of HSP90 were inversely associated with short-term efficacy in GC patients who had received fluorouracil/platinum-based advanced first-line treatment. When first-line therapy failed, plasma HSP90 levels in patients with GC were significantly increased. In terms of progression-free survival (PFS), patients with GC or CRC who had low levels of HSP90 were not significantly different from those with high levels of HSP90. Univariate and multivariate analyses demonstrated that HSP90 was not an independent prognostic predictor for GC and CRC patients with PFS. However, RAS mutation was an independent prognostic factor for poor PFS in CRC patients. Conclusions: Plasma HSP90 levels have potential diagnostic value in advanced gastrointestinal carcinoma and therapeutic predictive value in GC.

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Section: Discussionmentioning

confidence: 97%

Diagnostic, clinicopathologic, therapeutic and prognostic value of Plasma Heat Shock Protein 90 levels in patients with advanced Gastrointestinal Carcinoma

Zhang¹,

Ni²,

Li³

et al. 2020

J. Cancer

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“…Additionally, the association between the HSP family and KRAS has been previously reported. Bar et al reported that HSP90 expression is associated with KRAS mutation and worse clinical parameters in CRC (22). The HSP family, including HSP27, may play certain roles in association with KRAS, which warrants further investigation.…”

Section: Model Of Acquired Resistance To 5-fluorouracil (5-fu) In Wid...mentioning

confidence: 99%

Inhibition of Heat-shock Protein 27 Reduces 5-Fluorouracil-acquired Resistance in Human Colon Cancer Cells

et al. 2021

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Background/Aim: In previous work we showed that expression of heat-shock protein 27 (HSP27; encoded by HSPB1) was associated with inherent resistance to . However, the relationship between HSP27 and acquired resistance remains unknown. Materials and Methods: We generated an acquired resistance model (WiDr-R) of a colon cancer cell line by exposing WiDr cells to 5-FU. Cell viability assays under treatment with 5-FU, as well as down-regulation of HSP27 using small interfering HSP27 RNA, were performed. HSP27 mRNA and protein expression was analyzed using real-time polymerase chain reaction and western blotting. Results: 5-FU-acquired resistance induced overexpression of HSP27 mRNA and protein levels in WiDr-R cells. Furthermore, siRNA knockdown of HSP27 in WiDr-R cells reduced 5-FUacquired resistance. Conclusion: These findings demonstrate that HSP27 is associated with 5-FU resistance in human colon cancer cell cells and suggest that HSP27 regulation represents a novel approach to overcoming chemoresistance in colorectal cancer.Colorectal cancer (CRC) is a very common disease worldwide. In advanced cancer, systemic chemotherapy and surgery are key treatment approaches. Currently, systemic chemotherapy for CRC has progressed remarkably. 5-Fluorouracil (5-FU) is a classic and very important cytotoxic anticancer drug; this treatment is commonly combined with other cytotoxic drugs such as oxaliplatin, and irinotecan. Furthermore, a paradigm shift has occurred in the use of molecular target drugs. Administration of vascular endothelial growth factor inhibitors (bevacizumab/ramucirumab) and epidermal growth factor receptor (EGFR) inhibitors (cetuximab/panitumumab) has improved the prognosis of advanced unresectable or recurrent CRC by up to approximately 30 months (1-3).However, resistance to 5-FU-based chemotherapy, which is widely used to treat CRC, remains an insurmountable clinical challenge. Therefore, novel approaches to overcoming 5-FU resistance are required, for which several strategies and drugs have been identified (4-6). Heat-shock proteins, including heat-shock protein 27 (HSP27; encoded by HSPB1), act as molecular chaperones in protein-protein interactions under physiological conditions. Additionally, HSP27 expression is increased in various types of malignant diseases (7-9). Furthermore, a relationship between HSP27 overexpression and drug resistance has been reported (9-11). We have previously suggested that HSP27 is associated with 5-FU resistance in certain human colon cancer cell lines. Cell lines with higher levels of HSP27 expression showed a higher degree of 5-FU resistance compared to those with lower expression levels (12). Additionally, in experiments using cell lines with high HSP27 expression (inherently resistant to 5-FU according to our hypothesis), downregulation of HSP27 using small interfering RNA (siRNA) or short hairpin RNA reduced 5-FU resistance (12, 13). Furthermore, in the same setting, down-regulation of HSP27 using apatorsen, an antisense oligonucleotide that targets HSP27, reduced...

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Introns control stochastic allele expression bias

2021

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Monoallelic expression (MAE) or extreme allele bias can account for incomplete penetrance, missing heritability and non-Mendelian diseases. In cancer, MAE is associated with shorter patient survival times and higher tumor grade. Prior studies showed that stochastic MAE is caused by stochastic epigenetic silencing, in a gene and tissue-specific manner. Here, we used C. elegans to study stochastic MAE in vivo. We found allele bias/MAE to be widespread within C. elegans tissues, presenting as a continuum from fully biallelic to MAE. We discovered that the presence of introns within alleles robustly decreases MAE. We determined that introns control MAE at distinct loci, in distinct cell types, with distinct promoters, and within distinct coding sequences, using a 5’-intron position-dependent mechanism. Bioinformatic analysis showed human intronless genes are significantly enriched for MAE. Our experimental evidence demonstrates a role for introns in regulating MAE, possibly explaining why some mutations within introns result in disease.

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The Association Between HSP90/topoisomerase I Immunophenotype and the Clinical Features of Colorectal Cancers in Respect to KRAS Gene Status

Abstract: Our results revealed that cooperation between HSP90 and Topo I expression exists in CRCs, independently of KRAS gene status, suggesting that co-expression of both proteins might be considered as a double target on individual tumor cells.

Cited by 3 publications

References 22 publications

Diagnostic, clinicopathologic, therapeutic and prognostic value of Plasma Heat Shock Protein 90 levels in patients with advanced Gastrointestinal Carcinoma

Diagnostic, clinicopathologic, therapeutic and prognostic value of Plasma Heat Shock Protein 90 levels in patients with advanced Gastrointestinal Carcinoma

Inhibition of Heat-shock Protein 27 Reduces 5-Fluorouracil-acquired Resistance in Human Colon Cancer Cells

Introns control stochastic allele expression bias

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