Studies of ionic mechanisms associated with human cancers
Author(s)
Guzel, Refika Mine
Type
Thesis
Abstract
The general aim of this thesis was to undertake a series of inter-related studies with a
view to improving our understanding of the role of ion channel expression and its
regulation in cancer cells with strong metastatic potential. The emphasis was on
neonatal Nav1.5 (nNav1.5) subtype of voltage-gated sodium channel (VGSC).
Chapter 1 (General Introduction) gives an account of the relevant literature and states
the main aims of the studies. Chapter 2 details the Materials and Methods, ranging
from quantitative molecular biology to in vitro assays of metastatic cell behaviour.
Chapter 3 presents experiments on regulation of VGSCs by insulin and insulin-like
growth factor1 (IGF1) in strongly metastatic human breast cancer (BCa) MDA-MB-
231 cells. The central strategy was to treat insulin and IGF1 as an integrated
signalling system (”IIS”) and suppress it using pharmacological inhibitors and RNAi.
Inhibiting IIS signalling suppressed metastatic cell behaviours (MCBs) and
decreased nNav1.5 expression and activity. Chapter 4 describes studies on mRNA
expression of a variety of cancer-associated ion channels (CAICs) in peripheral
blood of normal human subjects with a view to laying the foundations for subsequent
patient-based studies. The following 8 CAICs were studied: nNav1.5, VGSC-β1,
VGSC-β1b, Kv1.3, Kv10.1, Kv11.1, KCa3.1 and TRPM8. Several differences were
noted between healthy cases and cancer patients. In particular, nNav1.5 and Kv1.3
mRNA expressions were up- and down-regulated, respectively. Chapter 5 shows that
the anti-diabetic drug Metformin suppressed Matrigel invasion and nNav1.5 mRNA
expression in MDA-MB-231 cells. Chapter 6 involves studies on the strongly
metastatic human colorectal cancer (CRCa) SW-620 cells, which were found to
express nNav1.5 mRNA and protein. Silencing nNav1.5 expression had a significant
inhibitory effect on Matrigel invasion. The thesis ends with a General Discussion and
Conclusion chapter, integrating the findings in the context of the field at large and
pointing to future directions.
view to improving our understanding of the role of ion channel expression and its
regulation in cancer cells with strong metastatic potential. The emphasis was on
neonatal Nav1.5 (nNav1.5) subtype of voltage-gated sodium channel (VGSC).
Chapter 1 (General Introduction) gives an account of the relevant literature and states
the main aims of the studies. Chapter 2 details the Materials and Methods, ranging
from quantitative molecular biology to in vitro assays of metastatic cell behaviour.
Chapter 3 presents experiments on regulation of VGSCs by insulin and insulin-like
growth factor1 (IGF1) in strongly metastatic human breast cancer (BCa) MDA-MB-
231 cells. The central strategy was to treat insulin and IGF1 as an integrated
signalling system (”IIS”) and suppress it using pharmacological inhibitors and RNAi.
Inhibiting IIS signalling suppressed metastatic cell behaviours (MCBs) and
decreased nNav1.5 expression and activity. Chapter 4 describes studies on mRNA
expression of a variety of cancer-associated ion channels (CAICs) in peripheral
blood of normal human subjects with a view to laying the foundations for subsequent
patient-based studies. The following 8 CAICs were studied: nNav1.5, VGSC-β1,
VGSC-β1b, Kv1.3, Kv10.1, Kv11.1, KCa3.1 and TRPM8. Several differences were
noted between healthy cases and cancer patients. In particular, nNav1.5 and Kv1.3
mRNA expressions were up- and down-regulated, respectively. Chapter 5 shows that
the anti-diabetic drug Metformin suppressed Matrigel invasion and nNav1.5 mRNA
expression in MDA-MB-231 cells. Chapter 6 involves studies on the strongly
metastatic human colorectal cancer (CRCa) SW-620 cells, which were found to
express nNav1.5 mRNA and protein. Silencing nNav1.5 expression had a significant
inhibitory effect on Matrigel invasion. The thesis ends with a General Discussion and
Conclusion chapter, integrating the findings in the context of the field at large and
pointing to future directions.
Date Issued
2012
Date Awarded
2012-07
Advisor
Djamgoz, Mustafa
Keun, Factor
Publisher Department
Cell and Molecular Biology
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)