Transformation‐associated gene regulation by ATF6α during hepatocarcinogenesis

Abstract

We have previously reported that the endoplasmic reticulum (ER) stress-regulated transmembrane transcription factor 6 a (ATF6a) is implicated in the pathogenesis of hepatocellular carcinomas (HCCs). In order to further identify genes that are regulated by ATF6a, the global gene expression profiles of the ATF6a-transfected and untransfected HCC cell line, HLF, were analyzed. These results were then compared with the differential gene expression patterns of poorly differentiated HCC and control non-tumorous liver tissue. Our findings demonstrate that at least 18 genes are specifically upregulated by ATF6a, while another UPR mediator, XBP1 or ER-stress inducer, thapsigargin could partially stimulate or even repress some of them in HCC cells. Moreover, six of these identified genes contain potential ER stress-responsive elements and/or unfolded protein response elements in their 5 0 regulatory regions.

Activation of a system A amino acid transporter, ATA1/SLC38A1, in human hepatocellular carcinoma and preneoplastic liver tissues

“…Expression of ATA1, ATA2, and LAT1 mRNAs in five normal livers (normal), 25 HCCs and matched non-cancerous liver tissues. Total RNA extracts from these tissues were subjected to QRT-PCR as described (16). The relative mRNA expression levels were then calculated by normalizing with a ß 2 -microglobulin control.…”

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…So far, it has been demonstrated that ATF6 is required for the adaptation of dormant squamous carcinoma cells to nutritional stresses and in vivo microenvironment through the up-regulation of RHEB and activation of mTOR signaling (56). Moreover, as shown in the hepatocellular carcinoma model, ATF6 may be involved in the regulation of cell proliferation (57) or in the sensitivity to chemotherapy in leukemia cells (58). Data also suggest ATF6 contribution to cancer progression by shaping tumor microenvironment (59) as well as in the induction of the senescent phenotype (60).…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…ATF6α transactivates target genes that include ubiquitin-conjugating enzyme E2C (UBE2C) and CDKN3, which promote tumorigenesis (Arai et al 2006). Polymorphisms in ATF6a are associated with increased expression and hepatocellular carcinoma ).…”