Biovetenskaper och näringslära / Biosciences and Nutrition
Abstract
Integrins are the major transmembrane receptors for the extracellular
matrix (ECM) which regulate a diverse array of cellular functions crucial
to tumor cell migration, invasion, proliferation and survival. Integrins
contact the ECM via their N-terminal extracellular domains and connect to
the intracellular environment via the C-terminal cytoplasmic domains.
Therefore, studies on the integrins cytoplasmic domain binding proteins
will help to better understand the mechanisms of tumor progression and
make them appealing targets for cancer therapy. Kindlin and PAK
(p21-activated kinase) family proteins have been identified as
integrin-interacting proteins. The following studies in this thesis aimed
to investigate the role of Kindlin-2 and PAK5 in human cancer
progression.
In paper I, we investigated the expression of Kindlin-2 in a series of
malignant mesothelioma (MM) and found it to be highly expressed and
correlated to tumor cell proliferation. To evaluate the biological
relevance of Kindlin-2 in MM, we also evaluated ILK (integrin-linked
kinase) and Kindlin-1 expression levels. Notably, in vitro depletion of
Kindlin-2 impaired tumor cell adhesion and migration. Our findings
provide new evidence that Kindlin-2 contributes to MM progression and may
therefore be a potential target for anti-cancer therapy in MM.
In paper II, we demonstrated a novel role of Kindlin-2 as a signaling
molecule that controls a Wnt-paralleling signaling pathway. We showed
that Kindlin-2 specifically activates small GTPase Cdc42, but not Rac1
and RhoA, and regulates beta-catenin activation via a Cdc42 -PAR 6
-PKCzeta -GSK-3beta cascade. Overexpression of Kindlin-2 in zebrafish
embryo xenograft promotes tumor growth, invasion and dissemination.
Importantly, overexpression of Kindlin-2 correlates to a poor prognosis
in malignant mesothelioma patients, suggesting an important role of
Kindlin-2 in cancer progression. Our data indicates that Kindlin-2
controls a signaling pathway that regulates tumor cell invasive growth.
In paper III, we used the human prostate cancer cell line PC-3 as a
working model and to analyze the role of Kindlin-2 in cell cycle
regulation by a loss-of-function approach. We found that depletion of
Kindlin-2 causes mitotic arrest during metaphase, with cyclin B1
accumulation, mitotic spindle disruption, γ tubulin mislocation and
abnormal chromosome formation. In addition, we demonstrated that
Kindlin-2 is involved in Cdc42 mediated functions at metaphase. Our
results identify a novel role of Kindlin-2 in the regulation of cell
cycle progression in mitosis.
In paper IV, we showed that PAK5 was overexpressed in colorectal
carcinoma (CRC) and associated with CRCs progression from adenoma to
carcinoma. Overexpression of PAK5 also correlated to CRC development from
lower Duke s grades to higher grades and correlated to CRC cell
differentiation. Depletion of PAK5 reduced CRC cell adhesion but promoted
their migration. Our study demonstrated that PAK5 expression correlates
to CRC progression and that PAK5 promotes CRC metastasis by regulating
CRC cell adhesion and migration.
Taken together, our studies highlight the importance of Kindlin-2 and
PAK5 association with human cancer. This work also strengthens the link
between Kindlin-2 and PAK5 expression and tumor malignancy in general,
and therefore, promotes Kindlin-2 and PAK5 as novel putative targets for
anti-cancer therapies