Transcriptome analysis of human cancer reveals a functional role of Heme Oxygenase-1 in tumor cell adhesion

Abstract

BackgroundHeme Oxygenase-1 (HO-1) is expressed in many cancers and promotes growth and survival of neoplastic cells. Recently, HO-1 has been implicated in tumor cell invasion and metastasis. However, the molecular mechanisms underlying these biologic effects of HO-1 remain largely unknown. To identify a common mechanism of action of HO-1 in cancer, we determined the global effect of HO-1 on the transcriptome of multiple tumor entities and identified a universal HO-1-associated gene expression signature.ResultsGenome-wide expression profiling of Heme Oxygenase-1 expressing versus HO-1 silenced BeWo choriocarcinoma cells as well as a comparative meta-profiling of the preexisting expression database of 190 human tumors of 14 independent cancer types led to the identification of 14 genes, the expression of which correlated strongly and universally with that of HO-1 (P = 0.00002). These genes included regulators of cell plasticity and extracellular matrix (ECM) remodeling (MMP2, ADAM8, TGFB1, BGN, COL21A1, PXDN), signaling (CRIP2, MICB), amino acid transport and glycosylation (SLC7A1 and ST3GAL2), estrogen and phospholipid biosynthesis (AGPAT2 and HSD17B1), protein stabilization (IFI30), and phosphorylation (ALPPL2). We selected PXDN, an adhesion molecule involved in ECM formation, for further analysis and functional characterization. Immunofluorescence and Western blotting confirmed the positive correlation of expression of PXDN and HO-1 in BeWo cancer cells as well as co-localization of these two proteins in invasive extravillous trophoblast cells. Modulation of HO-1 expression in both loss-of and gain-of function cell models (BeWo and 607B melanoma cells, respectively) demonstrated a direct relationship of HO-1 expression with cell adhesion to Fibronectin and Laminin coated wells. The adhesion-promoting effects of HO-1 were dependent on PXDN expression, as loss of PXDN in HO-1 expressing BeWo and 607B cells led to reduced cell attachment to Laminin and Fibronectin coated wells.ConclusionsCollectively, our results show that HO-1 expression determines a distinct 'molecular signature' in cancer cells, which is enriched in genes associated with tumorigenesis. The protein network downstream of HO-1 modulates adhesion, signaling, transport, and other critical cellular functions of neoplastic cells and thus promotes tumor cell growth and dissemination.

Identifying and targeting determinants of melanoma cellular invasion

“…Although PXDN was expressed in melanoma samples its physiological role remains largely unexplored. Silencing PXDN in mesenchymal melanoma cells blocked cellular invasion and this observation is consistent with a previous study showing that loss of PXDN in BeWo choriocarcinoma cells blocked cellular invasion and adhesion [32]. Transforming growth factor – β1 (TGF-β1) treatment induced the production of PXDN by differentiating myofibroblasts undergoing an EMT during tissue fibrosis [50].…”

Lysophospholipid acyltransferases

“…Further studies are needed to address the issue of plasma LPA levels and increased AGPAT2 expression in ovarian cancer to refine the treatment and prognosis of ovarian cancer. A recent comparative meta-profiling analysis of 190 human tumors of 14 different types (breast, pancreas, lung, bladder, ovary, melanoma, uterus, renal, prostate, central nervous system, lymphoma, colorectal, mesothelioma and leukemia) identified increased expression of AGPAT2 [57]. A recent report found that knocking down AGPAT2 expression by siRNA inhibited tumor growth in an orthotopic xenograft model of human osteosarcoma [58].…”

A gene expression signature for defining aggressive phenotype and prognosis in intermediate-risk acute myeloid leukemia

“…PXDN, a member of the larger peroxidase gene family, is an adhesion molecule involved in ECM formation (Peterfi et al 2014;Tauber et al 2010). It is one of the target genes of miR-29a.…”