ABCC9 Is Downregulated and Prone to Microsatellite Instability on ABCC9tetra in Canine Breast Cancer.

Pan Hao,Xiao-Jun Huang,De-Ji Yang,Kai-Yue Song,Si-Qi Wang,Da-Wei Yao

doi:10.3389/fvets.2021.819293

Pan Hao, Xiao-Jun Huang + Show 4 more

Open Access

https://doi.org/10.3389/fvets.2021.819293

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Abstract

Tumorigenesis is associated with metabolic abnormalities and genomic instability. Microsatellite mutations, including microsatellite instability (MSI) and loss of heterozygosity (LOH), are associated with the functional impairment of some tumor-related genes. To investigate the role of MSI and LOH in sporadic breast tumors in canines, 22 tumors DNA samples and their adjacent normal tissues were evaluated using polyacrylamide gel electrophoresis and silver staining for 58 microsatellites. Quantitative real-time polymerase chain reaction, promoter methylation analysis and immunohistochemical staining were used to quantify gene expression. The results revealed that a total of 14 tumors (6 benign tumors and 8 breast cancers) exhibited instability as MSI-Low tumors. Most of the microsatellite loci possessed a single occurrence of mutations. The maximum number of MSI mutations on loci was observed in tumors with a lower degree of differentiation. Among the unstable markers, FH2060 (4/22), ABCC9tetra (4/22) and SCN11A (6/22) were high-frequency mutation sites, whereas FH2060 was a high-frequency LOH site (4/22). The ABCC9tetra locus was mutated only in cancerous tissue, although it was excluded by transcription. The corresponding genes and proteins were significantly downregulated in malignant tissues, particularly in tumors with MSI. Furthermore, the promoter methylation results of the adenosine triphosphate binding cassette subfamily C member 9 (ABCC9) showed that there was a high level of methylation in breast tissues, but only one case showed a significant elevation compared with the control. In conclusion, MSI-Low or MSI-Stable is characteristic of most sporadic mammary tumors. Genes associated with tumorigenesis are more likely to develop MSI. ABCC9 protein and transcription abnormalities may be associated with ABCC9tetra instability.

Highlights

Tumorigenesis is a complex multistep process associated with metabolic abnormalities and genomic instability [1]
The KATP channel is controlled by G proteins and allows potassium to flow into the cell
The sequencing result verified that the mutation form of MS in canine mammary tumors (CMTs) mainly included the insertion or deletion of nucleic acid fragments in repeated sequences

Summary

Introduction

Tumorigenesis is a complex multistep process associated with metabolic abnormalities and genomic instability [1]. Studies have shown that tumor cells differ significantly from normal cells in terms of ion channel expression activity and membrane potential [2, 3]. The adenosine triphosphate (ATP)-binding cassette subfamily C, member 9 (ABCC9) can be matched with potassium channel proteins Kir6.1 (KCNJ8) or Kir6.2 (KCNJ11) to assemble. ABCC9 Is Regulated in CMTs. ATP sensitive K+ channels (KATP) in the heart, pancreaticislets, skeletal muscle and smooth muscle [5]. The KATP channel is controlled by G proteins and allows potassium to flow into the cell. Previous studies have found that blocking the activity of KATP channels can significantly inhibit the proliferation of glioma and xenografted cells, inhibit the cell cycle at the G0/G1 phase, and induce apoptosis [6, 7]. The opening of KATP located on the mitochondrial membrane can attenuate cell apoptosis by maintaining the mitochondrial membrane potential [8]

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