Page 219 - Vitamin D and Cancer

206 F.S.G. Cheung and J.K.V. Reichardt

in vitro findings that the stratum basale with the least differentiated keratinocytes have
the highest levels of CYP27B1 and VDR [149, 166]. Therefore, disturbance to the
process of 1,25(OH) D mediated expression of these essential proteins for differentia-
2 3
tion can lead to diseases of the skin including cancer.

9.5.3 The Role of Vitamin D in Regulating Proliferation
and Differentiation in Skin Cancer

Transformed keratinocytes in squamous cell carcinomas (SCC) are not responsive
to the differentiation and proliferation effects of 1,25(OH) D [138]. The vitamin D
2
3
receptor interacting protein (DRIP) (DRIP205 is the major subunit for anchoring
the complex to the VDR) and steroid receptor co-activators (SRC) including SRC
2 and 3 are the two main co-activator complexes that interact with the VDR in
keratinocytes to initiate the transcription of the differentiation markers [43].
A model was initially proposed that DRIP205 complex dominates in binding with
the VDR during the proliferation/early differentiation stages and SRC complex is
the one dominating in late differentiation stages [117]. It was also found that SCC
overexpresses DRIP205 and hence it was thought that this elevation of DRIP205
levels inhibited the switch to SRC maintaining these transformed cells in a prolif-
eration state [15]. However, a follow up study [64] proved that this proposed model
of switching from DRIP205 to SRC is inadequate. The results from the follow up
study suggested that knock down of VDR, DRIP205 and SRC significantly
decreased the early marker keratin 1 and late markers loricrin and filaggrin.
However, only the knock down DRIP205 significantly reduced the early marker
keratin 10 and the intermediate marker involucrin. Thus, this latest study show that
VDR, DRIP and SRC are all required for induction of both early and late differen-
tiation markers. Also, the recruitment of the appropriate co-activator by the
1,25(OH) D -VDR complex is gene specific and not differentiation stage specific.
2
3
Further investigations are required to fully elucidate the keratinocyte differentiation
process in order to suggest targets for drug treatments.
It is known that activated Ras oncogenes can contribute to the development of
SCC and basal cell carcinoma (BCC) [41, 146, 157]. An immortalized squamous
cell line with activated Ras oncogene, HPK1A Ras, was compared to the original
immortalized squamous cell line (HPK1A) to investigate how keratinocytes can
exhibit 1,25(OH) D resistance in growth with respect to the Ras oncogene [58].
3
2
It was found that the ability of 1,25(OH) D to induce trans-activation for growth
3
2
inhibition was significantly decrease in HPK1A Ras compared to HPK1A cells.
The growth inhibition by 1,25(OH) D on HPK1A Ras cells was restored by the
3
2
addition of a MAPK kinase inhibitor. These results were reproducible when tested
with a reporter gene containing an upstream VDRE. An antibody to the binding
domain for the RXR yield a super shift only in HPK1A cells and follow up experi-
ments using anti-phosphothreonine and anti-phosphoserine antibody demonstrated
serine phosphorylation of RXR only in HPK1A Ras cells. In addition, serine