Page 214 - Vitamin D and Cancer

9 Molecular Biology of Vitamin D Metabolism and Skin Cancer 201

2+
calbindin carries Ca from the entry side to the basolateral membrane of the
2+
intestinal cell where it exits to the lamina propria via the plasma membrane Ca
2+
pump and the Na /Ca exchanger. Apart from this mechanism, 1,25(OH) D can
+
2 3
also cause rapid absorption of calcium (called transcaltachia) via binding of a mem-
brane receptor to activate the rapid non genomic pathway [113], also described
earlier in Sect. 9.3.3. A negative feedback loop exists through high levels of calcium
and 1,25(OH) D levels to regulate and decrease the level of PTH [98].
2 3
Calcium homeostasis is also important in maintaining bone health. The normal
bone remodeling cycle begins with the resorption of existing bone by osteoclasts
followed by the synthesis of unmineralized bone by osteoblasts (osteoid). With
adequate levels of 1,25(OH) D and mineral, the osteoblast mineralizes the osteoid
2 3
[116]. The differentiation, development, activation and survival of the osteoclast
depend on the binding of the receptor activator of NF-kB ligand (RANKL) on
the surface of preosteoblastic cells to RANK on the osteoclastic precursor cells. On
the other hand, this process can be blocked by the binding of osteoprotegrin (OPG)
to RANK to inhibit its binding to RANKL [18]. 1,25(OH) D plays a role in osteo-
2 3
clastogenesis by upregulating and repressing of RANKL and OPG expression
respectively [147] (Table 9.1). PTH also increases RANKL and decreases OPG
production [92], thus, 1,25(OH) D may also indirectly enhance osteoclastogenesis
2 3
by its influence on PTH levels. Therefore, PTH can enhance osteoclastogenesis to
release bone minerals into the circulation to maintain calcium homeostasis. During
times of adequate/high calcium in the circulation, PTH decreases and bone miner-
alization occurs by utilizing the mineral in the circulation. Thus PTH and
1,25(OH) D co-operate to coordinately regulate bone remodeling and calcium
2 3
homeostasis. Vitamin D is well known for its role in mineral and bone homeostasis;
however, epidemiological studies seem to suggest another role for this hormone.

9.4 Epidemiological Evidence on the Relationship
of Sun exposure and Cancer

9.4.1 Epidemiologic Evidence on the Role
of 1,25-Dihydroxyvitamin D in Skin Cancer
3

The three common types of skin cancers include melanoma and two nonmelano-
cytic skin cancers, squamous cell carcinoma (SCC) and basal cell carcinoma
(BCC). It is clear that UVR produces harmful photoproducts in DNA (Sect. 9.2)
and increase in sun exposure leading to increase in skin cancer risk has been sup-
ported by many studies [4, 119]. Migrant studies have examined the effect of
migration from an area of low ambient solar UV radiation to one of high ambient
solar radiation. The risk of each type of skin cancer was greater for native-born
Australians than for migrants [47, 86]. The rates were similar in people who
migrated in Australia (a high ambient solar radiation area) before 10 years of age