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Journal of Cancer Research and Clinical Oncology

Erschienen in:

02.06.2021 | Original Article – Cancer Research

High nuclear expression of HIF1α, synergizing with inactivation of LIMD1 and VHL, portray worst prognosis among the bladder cancer patients: association with arsenic prevalence

verfasst von: Mukta Basu, Amvrin Chatterjee, Balarko Chakraborty, Essha Chatterjee, Sabnam Ghosh, Sudip Samadder, Dilip Kumar Pal, Anup Roy, Jayanta Chakrabarti, Amlan Ghosh, Chinmay Kumar Panda

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 8/2021

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Abstract

Purpose

Our study was aimed to understand the importance of LIMD1-VHL-HIF1α pathway in development of bladder carcinoma (BlCa) in association with arsenic prevalence.

Methods

At first, the mRNA expression pattern of the genes of this pathway (LIMD1, VHL and HIF1α) was checked in GEO datasets and in our samples. Next, genetic and epigenetic profiling of LIMD1 and VHL was done in our sample pool, validated in T24 BlCa cell line. The results were next correlated with various clinico-pathological parameters.

Results

Differential under-expression of LIMD1 and VHL genes was found in muscle-invasive BlCa (MIBC) in comparison to non-muscle-invasive BlCa (NMIBC). However, HIF1α protein, but mRNA, was found to be overexpressed among the MIBC samples; depicting the probability of HIF1α protein stabilization. Analysis of genetic and epigenetic profiles of LIMD1 and VHL exposed a frequent promoter methylation of LIMD1 gene in MIBC samples. Further, in-depth look into the results unveiled that the high nuclear expression of HIF1α was significantly correlated with genetic alterations of LIMD1, alone or in combination with VHL. Moreover, treating the T24 cells with a de-methylating agent (5-aza-2′-deoxycytidine) re-expressed the methylated LIMD1 and VHL genes, which in turn, reduced the HIF1α protein level significantly. Additionally, patients with high arsenic content (> 112 ng/g, AsH) seemed to have recurrent promoter methylation in LIMD1, as well as co-methylation/alteration of LIMD1 and VHL gene. Lastly, high nuclear expression of HIF1α in association with co-alteration of VHL and LIMD1 showed the worst overall survival (OS) among the patients.

Conclusion

To conclude, MIBC samples portrayed higher alterations in VHL and LIMD1, thereby, stabilizing HIF1α protein and lowering the OS of patients.

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Titel: High nuclear expression of HIF1α, synergizing with inactivation of LIMD1 and VHL, portray worst prognosis among the bladder cancer patients: association with arsenic prevalence
verfasst von: Mukta Basu
Amvrin Chatterjee
Balarko Chakraborty
Essha Chatterjee
Sabnam Ghosh
Sudip Samadder
Dilip Kumar Pal
Anup Roy
Jayanta Chakrabarti
Amlan Ghosh
Chinmay Kumar Panda
Publikationsdatum: 02.06.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 8/2021
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-021-03661-z

Springer Medizin

High nuclear expression of HIF1α, synergizing with inactivation of LIMD1 and VHL, portray worst prognosis among the bladder cancer patients: association with arsenic prevalence