Functional Analysis of Novel Sonic Hedgehog Gene Mutations Identified in Basal Cell Carcinomas from Xeroderma Pigmentosum Patients

Abstract

Altered sonic hedgehog (SHH) signaling is crucial in the development of basal cell carcinomas (BCC), the most common human cancer. Mutations in SHH signal transducers, PATCHED and SMOOTHENED, have already been identified, but SHH mutations are extremely rare; only 1 was detected in 74 sporadic BCCs. We present data showing unique SHH mutations in BCCs from repair-deficient, skin cancer-prone xeroderma pigmentosum (XP) patients, which are characterized by high levels of UV-specific mutations in key genes involved in skin carcinogenesis, including PATCHED and SMOOTHENED. Thus, 6 UV-specific SHH mutations were detected in 5 of 33 XP BCCs. These missense SHH alterations are not activating mutations for its postulated proto-oncogene function, as the mutant SHH proteins do not show transforming activity and induce differentiation or stimulate proliferation to the same level as the wild-type protein. Structural modeling studies of the 4 proteins altered at the surface residues, G57S, G64K, D147N, and R155C, show that they do not effect the protein conformation. Interestingly, they are all located on one face of the compact SHH protein suggesting that they may have altered affinity for different partners, which may be important in altering other functions. Additional functional analysis of the SHH mutations found in vivo in XP BCCs will help shed light on the role of SHH in skin carcinogenesis. In conclusion, we report for the first time, significant levels of SHH mutations found only in XP BCCs and none in squamous cell carcinomas, indicating their importance in the specific development of BCCs.

Activation of Sonic Hedgehog Signaling Pathway in Olfactory Neuroblastoma

“…The sonic hedgehog (Shh) signaling pathway has been demonstrated to regulate embryo development and tumor cell proliferation in several human neoplasms, such as the prostate, pancreas and skin carcinomas [7,8,9,10]. Shh is a member of the hedgehog family that was originally identified by its homology to the Drosophila melanogaster segment polarity gene, hedgehog.…”

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis

“…Recent studies suggest that the hedgehog (Hh) signal pathway contributes to cell proliferation and differentiation in several human neoplasms, such as pancreas, prostate and skin carcinomas. (6)(7)(8) The Hh gene was first identified in the embryonic development of Drosophila. (9) The Hh signal transduction pathway controls a variety of developmental processes such as proliferation, differentiation and organogenesis.…”

“…(9)(10)(11) It is known that Gorlin's syndrome, which is associated with abnormal activation of the Hh signal pathway mainly due to Ptch mutation, shows an increased incidence of basal cell carcinoma, medulloblastma and rhabdomyosarcoma. (8,12) There are no available data on the expression of Hh signal molecules in human epithelial ovarian neoplasms. Therefore, in the present study we first investigated immunohistochemically the expression of Hh molecules, such as Shh, Ihh, Dhh, Ptch, Smo and Gli1 proteins, in benign, borderline and malignant ovarian tumors and normal ovarian surface epithelium (OSE), and correlated the expression of each with cell proliferative activity assessed by Ki-67 staining, clinicopathological parameters and patient outcomes.…”

Early recognition of basal cell naevus syndrome

“…Therefore it is not surprising that activating SMO mutations have been detected in a number of sporadic BCCs [31]. Recently, CouvePrivat et al [4] identified SHH missense mutations in BCCs from xeroderma pigmentosum patients. All the BCCs with SHH mutations also had alterations in either SMO or PTCH, indicating that the SHH mutations may represent an additive effect on the oncogenic potential.…”