Abstract
Breast cancer is the most commonly diagnosed cancer in women, and the second most
frequent cause of death from cancer in women. Pancreatic ductal adenocarcinoma
(PDAC) is one of the deadliest forms of cancer with only a 5% 5-year survival rate. Both
types of cancer form solid tumors, characteristics of which are a shift towards glycolytic
metabolism and increased acid production. HER2 receptor overexpression in breast
cancer leads to further increased glycolysis, invasion and metastasis, drug resistance and
poor prognosis. Increased tumor glycolysis requires acquisition of mechanisms for dealing with excess acid production. In this light, evidence accumulates on the importance of pH regulatory proteins to cancer cell survival and motility.
Our group previously demonstrated upregulation of the Na+/HCO3 - co-transporter NBCn1 (SLC4A7) by a constitutively active form of HER2 receptor (p95HER2). In Paper 1 and Paper 3 we demonstrate mechanisms of p95HER2-dependent NBCn1 upregulation.
Transcriptionally, NBCn1 expression is controlled by ERK1 and Akt1 kinases modulating
Krüppel-like factor 4 (KLF4) transcriptional activity. Additionally, we show that other HER2 family members, when stimulated, are able to upregulate NBCn1 expression as well. Paper 3 demonstrates that p95HER2 further stabilizes NBCn1 mRNA, by preventing its downregulation through a 3’UTR region-dependent mechanism, probably involving
miRNAs. In Paper 5 we investigate miRNA expression profiles induced by full-HER2
receptor and p95HER2 and demonstrate that despite major similarities, a group of
miRNAs are differentially regulated by full-length HER2 and p95HER2. Additionally, we
demonstrate that p95HER2 downregulates a member of the c-myb family of transcription
factors, MYBL1, through an oncogenic miR-221/222 pathway.
Paper 2 reviews current findings on two families of bicarbonate transporters – SLC4 and
SLC26, in cancer. Moreover, using analysis of publicly available high-throughput data we
hypothesize that expression and, perhaps, function, of SLC4 and SLC26 family members,
as well as carbonic anhydrase (CA) II, IX and XII is cancer subtype specific. In Paper 4 we show that a3, subunit of another pH-regulatory protein complex - V-ATPase, is upregulated at the mRNA and protein level in a panel of PDAC cancer cell lines. We
demonstrate the importance of the a3 subunit for proliferation and survival pathways,
motility and invasion in PDAC cells. As increased expression of a3 was detected in every
PDAC cell line tested, we propose a3 as a potential target for diagnostics and targeted
therapy.
Collectively, our findings demonstrate several novel mechanisms through which the
expression of a pH-regulatory protein, NBCn1, can be controlled by an oncogene,
p95HER2. Further, they reveal differences in small non-coding RNA (miRNA) expression
profiles between full-length HER2 and its truncated p95HER2 form. And finally, we report a potential target for PDAC diagnostics and treatment
frequent cause of death from cancer in women. Pancreatic ductal adenocarcinoma
(PDAC) is one of the deadliest forms of cancer with only a 5% 5-year survival rate. Both
types of cancer form solid tumors, characteristics of which are a shift towards glycolytic
metabolism and increased acid production. HER2 receptor overexpression in breast
cancer leads to further increased glycolysis, invasion and metastasis, drug resistance and
poor prognosis. Increased tumor glycolysis requires acquisition of mechanisms for dealing with excess acid production. In this light, evidence accumulates on the importance of pH regulatory proteins to cancer cell survival and motility.
Our group previously demonstrated upregulation of the Na+/HCO3 - co-transporter NBCn1 (SLC4A7) by a constitutively active form of HER2 receptor (p95HER2). In Paper 1 and Paper 3 we demonstrate mechanisms of p95HER2-dependent NBCn1 upregulation.
Transcriptionally, NBCn1 expression is controlled by ERK1 and Akt1 kinases modulating
Krüppel-like factor 4 (KLF4) transcriptional activity. Additionally, we show that other HER2 family members, when stimulated, are able to upregulate NBCn1 expression as well. Paper 3 demonstrates that p95HER2 further stabilizes NBCn1 mRNA, by preventing its downregulation through a 3’UTR region-dependent mechanism, probably involving
miRNAs. In Paper 5 we investigate miRNA expression profiles induced by full-HER2
receptor and p95HER2 and demonstrate that despite major similarities, a group of
miRNAs are differentially regulated by full-length HER2 and p95HER2. Additionally, we
demonstrate that p95HER2 downregulates a member of the c-myb family of transcription
factors, MYBL1, through an oncogenic miR-221/222 pathway.
Paper 2 reviews current findings on two families of bicarbonate transporters – SLC4 and
SLC26, in cancer. Moreover, using analysis of publicly available high-throughput data we
hypothesize that expression and, perhaps, function, of SLC4 and SLC26 family members,
as well as carbonic anhydrase (CA) II, IX and XII is cancer subtype specific. In Paper 4 we show that a3, subunit of another pH-regulatory protein complex - V-ATPase, is upregulated at the mRNA and protein level in a panel of PDAC cancer cell lines. We
demonstrate the importance of the a3 subunit for proliferation and survival pathways,
motility and invasion in PDAC cells. As increased expression of a3 was detected in every
PDAC cell line tested, we propose a3 as a potential target for diagnostics and targeted
therapy.
Collectively, our findings demonstrate several novel mechanisms through which the
expression of a pH-regulatory protein, NBCn1, can be controlled by an oncogene,
p95HER2. Further, they reveal differences in small non-coding RNA (miRNA) expression
profiles between full-length HER2 and its truncated p95HER2 form. And finally, we report a potential target for PDAC diagnostics and treatment
| Originalsprog | Engelsk |
|---|
| Forlag | Department of Biology, Faculty of Science, University of Copenhagen |
|---|---|
| Antal sider | 180 |
| Status | Udgivet - 2015 |
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