The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 231

deficiencies in g -radiation-induced cell cycle arrest, whereas Clock m/m MEFs
show lower levels of DNA synthesis and cell proliferation than wild-type con-
trols. 19,128 Together, the studies described above led to the conclusion that the
cancer-prone phenotypes discovered in Per2 m/m and Per2 / mice are a result
of the loss of a “non-clock function” of the Per2 gene and not the function of
the mammalian circadian clock. 6
3.3. The molecular clock suppresses tumor development
in mice
In contrast, we suggest that a more detailed analysis of the available information
supports a direct role for the molecular clock in tumor suppression in mice.
First, the observation of a temporary slowdown in Cry1 / ; Cry2 /
hepatocyte proliferation immediately after partial hepatectomy cannot predict
whether Cry1 / ; Cry2 / mice are tumor resistant under normal physiolog-
ical conditions. Surgical stress caused by partial hepatectomy can suppress the
growth of hepatocellular carcinoma in mouse livers until the third postoper-
ative day. 130 In fact, compared to wild-type controls, most mouse models
prone to spontaneous hepatocellular carcinoma show an initial delay in hepa-
tocyte proliferation after partial hepatectomy. For example, compared to
wild-type controls, mice lacking the nuclear receptor FXR display a delay
in hepatocyte proliferation after partial hepatectomy until the ninth postop-
erative day. However, Fxr / mice quickly regain the ability of rapid hepa-
tocyte proliferation and develop malignant liver tumors after 12 months of
age. 131,132 Since Cry1 / ; Cry2 / mice show significantly dampened Bmal1
expression and deregulation of the mitogen-activated protein kinase/extracel-
lular signal-regulated kinase (MAPK/ERK) pathway in the liver, 133-135 it
would be important to examine whether the temporary delay in hepatocyte
proliferation in Cry1 / ; Cry2 / mice after partial hepatectomy is caused by
deficiencies in cellular signaling essential for G1 cell cycle initiation. 136,137
Second, the conclusions that Per- mutants are cancer prone but Cry-
mutants are tumor resistant are confounded by significant differences in
the phenotypes of control wild-type and p53 -null mice but not Per - and
Cry -mutant mice in different studies. 29,124,127,128 For example, the conclu-
sion that a single 4-Gy sublethal dose of g -irradiation led to a similar rate of
decline in the survival of irradiated wild-type and Cry1 / ; Cry2 / mice
was based on an unusual sensitivity of wild-type mice to g -irradiation, 128
which was not observed in the earlier study indicating increased sensitivity
of the Per2 -mutant mice to the same 4-Gy sublethal g -radiation. 124