SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R C E L L B I O L O G Y P R O G R A M
CHIA-YANG LIU, PH.D.
Assistant Professor of Ophthalmology
DESCRIPTION OF RESEARCH
Dr. Liu’s research focuses on the roles of a
membrane/soluble glycoprotein complex
(Muc4/sialomucin complex, SMC), which is a
major contributing mucin at the ocular surface
and in the ocular tear film. Two specific aims
were designed to examine the biological function
of Muc4/SMC in vivo. The first aim is to generate
Muc4/SMC knockout (KO) mice to examine
its loss-of-function. Dr. Liu’s rationale is that
Muc4/SMC is composed of two subunits derived
from a single gene: an O-glycosylated mucin subunit
ASGP-1, which has been implicated in antiadhesion
phenomena at epithelial cell surfaces,
and a transmembrane subunit ASGP-2, which is
N-glycosylated, has two epidermal growth factorlike
(EGF-like) domains, and has been implicated
in ErbB2cellular signaling. Immunohistochemical
analyses have shown that Muc4/SMC is expressed
only in the cell layers of the superficial half of the
corneal and conjunctival epithelia. These results
have led the group to hypothesize that Muc4/
SMC acts as an intrinsic differentiation and survival
factor regulating the behavior of the cells in
those epithelia through its effects on ErbB2.
Muc4/SMC KO mice will be created via gene
targeting. This KO mouse strain can be used to
examine the biological function of Muc4/SMC
and can be used as an animal model to investigate
the pathogenesis of ocular surface disease such as
dry eye.
Dr. Liu’s second aim is to generate K14-
Muc4 transgenic mice to investigate Muc4/SMC
gain-of-function. His rationale is that a matured
corneal epithelium contains three types of cells
organized in five to six layers, which include basal
cells (one layer), supra-basal cells (two layers),
and superficial cells (two to three layers). These
three types of cells are phenotypically distinct in
terms of their proliferative activity and differentiative
status. The basal cells are relatively
proliferative, whereas the superficial cells are
post-mitotic and become terminally differentiated.
Since Muc4/SMC is expressed only in the
cell layers of the superficial half of the corneal
and conjunctival epithelia and Muc4/SMC can
induce cellular signaling through ErbB2 receptor,
it is hypothesized that Muc4/SMC-ErbB2 signaling
may play an important role in regulating
corneal epithelial differentiation, apoptosis, and
desquamation. To test this hypothesis, an epithelial
basal cell-specific promoter (K14 keratin
promoter) will be used to drive Muc4/SMC expression
in the K14-Muc4 transgenic (Tg) mice.
It is anticipated that in the K14-Muc4 Tg, Muc4/
SMC will be aberrantly over-expressed in basal
corneal epithelium, which in turn will affect the
corneal epithelium homeostasis. The K14-Muc4
Tg will allow Dr. Liu and his colleagues to investigate
the corneal epithelial cell biology. These
combined studies should help to provide them
with a more complete picture of the functions
of Muc4/SMC at the ocular surface as well as
insights into the roles of this mucin in ocular
surface diseases and aberrations.
SELECTED PUBLICATIONS
2002
Saika, S, Ohnishi, Y, Ooshima, A, Liu, CY, and
Kao, WW. Epithelial repair roles of extracellular
matrix. Cornea (2 Suppl 1): S23-S29, 2002.
Wang, IJ, Carlson, EC, Liu, CY, Kao, CW, Hu,
FR, and Kao, WW. Cis-regulatory elements of
the mouse Krt1.12 gene. Molecular Vision 8: 94-
101, 2002.
Austin, BA, Coulon, C, Liu, CY, Kao, WW, and
Rada, JA. Altered collagen fibril formation in the
sclera of lumican-deficient mice. Investigative
Ophthalmology & Visual Science 43:1695-1701,
2002.
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2004