Upregulated expression of periostin by hypoxia in non-small-cell lung
cancer cells promotes cell survival via the Akt/PKB pathway
Gaoliang Ouyang
a,
*
,1
, Min Liu
a,1
, Kai Ruan
a
, Gang Song
a,b
, Yubin Mao
a
, Shideng Bao
a
a
Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, China
b
Cancer Research Center, Medical College, Xiamen University, Xiamen 361005, China
article info
Article history:
Received 27 November 2008
Received in revised form 19 February 2009
Accepted 19 February 2009
Keywords:
Periostin
Hypoxia
Apoptosis
Cell survival
Akt
abstract
Periostin is a secreted protein and has been shown to be frequently overexpressed in var-
ious types of human cancers. We have previously reported that periostin potently pro-
motes metastatic growth of colon cancer by augmenting cell survival. However, little is
known about the functions of periostin in non-small-cell lung cancer. Here, we revealed
that increased expression of periostin in non-small-cell lung cancer A549 cells was one
kind of cellular responses to the stress of chemical-mimic hypoxia, and this effect could
be regulated by hypoxia inducible growth factors, such as TGF-
a
and bFGF. We further
demonstrated that RTK/PI3-K pathway activated by TGF-
a
and bFGF was evoked in upreg-
ulating the expression of periostin, and then periostin promoted the survival of A549 cells
under hypoxic microenvironment via activation of Akt/PKB pathway. Therefore, periostin
and the pathway that it involved might provide a target for lung cancer treatment.
Ó 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
In recent years there has been a growing awareness that
the cellular microenvironment throughout tumorigenesis
plays a critical role in providing supportive microsur-
roundings for cancer cell proliferation, survival, migration
and invasion [1–3]. A variety of responses are undertaken
in mammalian cells to maintain oxygen homeostasis, a
precise balance between the request for oxygen as an en-
ergy substrate for oxidative phosphorylation and other
essential metabolic reactions and the inherent risk of oxi-
dative damage to cellular macromolecules. However, oxy-
gen homeostasis can be disrupted through genetic,
epigenetic or somatic alterations in human tumors, and
thus resulting in a poorly vascularized microenvironment
[4,5]. After early neoplastic transformation, rapidly grow-
ing tumor cells routinely outstrip their supply of oxygen
and nutrients from the surrounding capillary vessels
caused by aberrant newborn blood vessels and poor blood
flow. Subsequently tumors will be exposed to the stressed
microenvironments characterized by chronic hypoxia, low
pH and nutrient starvation [5]. Many genes and epigeno-
types will alter to response to these stresses to promote
cellular survival, and finally initiate the late stage of tumor
progression angiogenesis and metastasis. However, many
of them are still unclear.
In our previous work to screen the divergent expression
genes in metastatic tumors, we have identified an interest-
ing gene which is turned out to be periostin [6]. Periostin is
a secreted protein that was originally isolated from
MC3T3-E1 osteoblast cells to modulate cell adhesion as
an extracellular matrix-associated molecule [7], and also
proved to be involved in new bone formation and wound
healing which is generally regulated by TGF-b [8]. It can
serve as a prognostic marker that is overexpressed in many
kinds of tumor tissues such as non-small-cell lung carcino-
mas [9–11], ovarian carcinoma [12], oral cancer [13], and
head and neck squamous cell carcinoma [14,15]. Particu-
larly in late-stage tumor progression, periostin functions
to bind
a
v
b
3
integrins to promote tumor metastasis via
activating the Akt/PKB cell survival signaling pathway
0304-3835/$ - see front matter Ó 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.canlet.2009.02.030
* Corresponding author. Tel.: +86 592 2186091; fax: +86 592 2188101.
E-mail address: oygldz@yahoo.com.cn (G. Ouyang).
1
These authors contributed equally to this work.
Cancer Letters 281 (2009) 213–219
Contents lists available at ScienceDirect
Cancer Letters
journal homepage: www.elsevier.com/locate/canlet