Modulation of ATP8B1 Gene expression in Colorectal Cancer Cells Suggest its Role as a Tumor Suppressor

Abstract

Sporadic colorectal cancer (CRC) develops through distinct molecular events. Loss of 18q chromosome is a conspicuous event in the progression of adenoma to carcinoma. There is limited information regarding the molecular effectors of this event. Earlier, we had reported ATP8B1 as a novel gene associated with CRC. ATP8B1 belongs to the family of P-type ATPases (P4 ATPase) that primarily function to facilitate the translocation of phospholipids. In this study, we attempt to implicate ATP8B1 gene located on chromosome 18q as a tumor suppressor gene. We studied indigenous patient data and confirmed the reduced expression of ATP8B1 in tumor samples. CRC cell lines were engineered with reduced and enhanced levels of ATP8B1 which provided a tool to study its role on cancer progression. Forced reduction of ATP8B1 expression either by CRISPR/Cas9 or shRNA was associated with increased growth and proliferation of CRC cell line - HT29. In contrast, overexpression of ATP8B1 resulted in reduced growth and proliferation of SW480 cell line. We generated a network of genes that are downstream of ATP8B1. Further, we provide predicted effect of modulation of ATP8B1 levels on this network and possible effect on fatty acid metabolism related genes. These results provide evidence in support of ATP8B1 being a tumor suppressor that may affect fatty acid metabolism in CRC.

Identification and validation of two hub genes involved in membranous nephropathy based on machine learning

“…ATP81 is an oncogene on chromosome 18q that has been found to be associated with a broad range of liver diseases, including cholestasis, progressive familial intrahepatic cholestasis, and benign recurrent intrahepatic cholestasis. In a recent study, Saleh Althenayyan et al found that downregulation of ATP8B1 was associated with the poor prognosis of colorectal cancer, and the upregulated expression of this gene in colorectal cancer cells inhibited their growth and increased the rate of cell apoptosis [43], while the underlying regulatory mechanism was not further explained. Zhang et al demonstrated that ATP8B1 knockdown rstly induced mitochondrial dysfunction, and then, promoted production of reactive oxygen species (ROS) in squamous cell carcinoma of the lung [44].…”