基底细胞癌分子生物学机制研究进展

基底细胞癌是最常见的皮肤恶性肿瘤。随着基因测序技术的进步,已发现多个基因参与基底细胞癌的发病机制。其中,PTCH1、SMO、GLI、SUFU的突变导致Hedgehog(HH)通路的异常激活、TP53基因突变与基底细胞癌关系最密切。此外,一些新基因及通路也参与基底细胞癌的形成及发展,包括Hippo-YAP通路、 MYCN/FBXW7基因、TERT基因、DPH3-OXNAD1基因等。本文回顾了近年来基底细胞癌研究的主要分子机制。     

Hedgehog信号通路与基底细胞癌

基底细胞癌是最常见的皮肤恶性肿瘤之一。近几年的研究发现Hedgehog信号通路中Hedge-hog基因、Patched基因、Smoothened基因及Gli基因等的突变使Hedgehog信号通路目的基因GLI2、WNT、HIP等的持续激活在基底细胞癌的发生发展中起关键性作用,因而调节这个通路的活性对治疗基底细胞癌有重要的指导意义。     

皮肤基底细胞癌分子生物学研究进展

基底细胞癌是一种常见的皮肤恶性肿瘤，一系列研究发现，信号基因PTCH的突变与基底细胞癌的发生有密切关系，这极大的促进了基底细胞癌分子生物学研究机制的进程，现将近几年来有关于基底细胞癌发生的分子机制研究情况做一综述。     

基底细胞痣综合征的分子遗传学进展

基底细胞痣综合征是一种罕见的常染色体显性遗传病,其致病基因为PTCH,定位于9q22.3-q31,目前共报道突变112个,突变位点与临床表型无关。PTCH基因是一种肿瘤抑制基因,编码的蛋白能诱导细胞凋亡和抑制细胞增殖;PTCH突变激活Hedgehog信号通路,导致细胞无限制的增殖。     

基底细胞癌的发病机制与临床治疗进展

基底细胞癌(BCC)是一种有局部破坏性的伴有基底细胞样分化的上皮瘤,是全世界范围内最常见的皮肤肿瘤,占皮肤非黑素瘤的80%。Sonic Hedgehong(SHH)信号通路的激活在BCC发展中至关重要,其他机制则直接或间接通过SHH通路影响BCC凋亡与分化促进肿瘤的形成。BCC的治疗根据肿瘤的大小和位置以及浸润程度决定,包括手术扩大切除、光动力疗法及分子靶向治疗等。部分BCC可导致患者鼻、眼眶、鼻窦、唾液腺和颅底等局部破坏,多学科团队(MDT)共同商讨对手术的成功有重要作用。     

Hippo通路下游信号分子YAP在皮肤疾病中的研究进展

Yes相关蛋白(YAP)是Hippo信号通路的转录共激活因子,在调节器官大小及组织恶变中起着重要作用。当Hippo信号通路受到抑制时可促使YAP活化,引起细胞增殖,抑制细胞凋亡,并使细胞密度、细胞分布发生变化。近来研究表明,在鳞状细胞癌、基底细胞癌、黑色素瘤等皮肤肿瘤及瘢痕增生中,YAP起着重要作用。本文将对YAP在皮肤疾病中的研究进展进行综述。     

痣样基底细胞癌综合征研究进展

痣样基底细胞癌综合征是一种罕见的常染色体显性遗传性疾病,目前发现的致病基因包括PTCH1和PTCH2,该病可有皮肤损害、口腔损害、骨骼损害、眼睛损害及中枢神经系统损害等,治疗上采取相应的综合性措施。     

Hedgehog信号通路与基底细胞癌

基底细胞癌是最常见的皮肤恶性肿瘤之一。近几年的研究发现Hedgehog信号通路中Hedgehog基因、Patched基因、Smoothened基因及Gli基因等的突变使Hedgehog信号通路目的基因GL12、WNT、HIP等的持续激活在基底细胞癌的发生发展中起关键性作用，因而调节这个通路的活性对治疗基底细胞癌有重要的指导意义。     

以Hedgehog信号通路为靶向治疗皮肤基底细胞癌的研究进展

基底细胞癌(BCC)是最常见的皮肤癌。虽然大多数基底细胞癌可以通过相对简单的外科手术方法获得治愈,但仍有相当一部分晚期BCC患者缺乏良好的临床治疗方案。Hedgehog信号通路在正常胚胎发育过程中发挥着重要作用,其功能异常与多种肿瘤有关。近年来Hedgehog信号通路在BCC发生中的关键机制得到揭示,针对Hedgehog信号通路的靶向抑制剂也应用于BCC的临床治疗。该文综述了BCC靶向治疗这个快速发展的领域中新的研究成果。     

痣样基底细胞癌综合征1例并文献复习

目的报道痣样基底细胞癌综合征(NBCCS)1例,总结其临床特点及治疗效果,提高对NBCCS的认识。方法报告2007年至2019年在甘肃省人民医院确诊的1例NBCCS患者的临床表现、影像学表现及病理检查结果,并复习相关文献。结果 NBCCS为罕见的常染色体显性遗传性疾病,由PTCH1、PTCH2等多种基因的显性突变引起。临床主要表现为多发性基底细胞癌、多发性颌骨角化囊肿、掌角化障碍和颅内异位钙化、面部畸形(畸形眼、唇腭裂、严重眼畸形)及骨骼系统异常、多器官发育障碍等。临床诊断主要依赖诊断标准,PTCH基因检测可证实诊断。NBCCS涉及多个器官系统,治疗需多学科综合管理,定期复查CT、MRI等明确病变进展情况。结论 NBCCS临床罕见,发病机制尚未明确。临床医师应提高对该病的认识,减少临床误诊。     

Correlations between the Sonic Hedgehog pathway and basal cell carcinoma

The Hedgehog (HH) family of intercellular signaling proteins has some essential functions in patterning both invertebrate and vertebrate embryos. Identified as an important regulator of segment polarity and tissue organization in flies, the HH pathway can also play a significant role in human development and in cutaneous carcinogenesis. The family received their name because when the D. melanogaster HH protein malfunctions the mutant fly ends up looking like a small prickly ball, similar to a curled up hedgehog. The Sonic hedgehog (SHH) pathway is implicated in the etiology of the most common human cancer, the basal cell carcinoma (BCC). Mutations in the receptor of SHH, the patched gene (PTCH), have been characterized in sporadic BCCs as well as those from patients with the rare genetic syndrome nevoid BCC. Human PTCH is mutated in sporadic as well as hereditary BCCs, and inactivation of this gene is probably a necessary if not sufficient step for tumorigenesis. Delineation of the biochemical pathway in which PTCH functions may lead to rational medical therapy for skin cancer and possibly other tumors.     

Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas

BACKGROUND: Basal cell carcinoma (BCC) of the skin is the most common human cancer. The genetic alterations underlying BCC development are only partly understood. OBJECTIVES: To investigate further the molecular genetics of sporadic BCCs, we performed mutation analyses of 10 skin cancer-associated genes in 42 tumours. METHODS: Single-strand conformational polymorphism analysis followed by DNA sequencing was used to screen for mutations in the sonic hedgehog pathway genes PTCH, SMOH, SUFUH and GLI1, in the TP53 tumour suppressor gene, and in the proto-oncogenes NRAS, KRAS, HRAS, BRAF and CTNNB1. Microsatellite markers flanking the PTCH, SUFUH and TP53 loci at 9q22, 10q24 and 17p13, respectively, were studied for loss of heterozygosity (LOH). RESULTS: PTCH mutations were found in 28 of 42 tumours (67%). Microsatellite analysis revealed LOH on 9q22 in 20 of 38 tumours investigated (53%), including 14 tumours with and six tumours without PTCH mutations. SMOH mutations were identified in four of the 42 BCCs (10%) while two tumours demonstrated mutations in SUFUH, including one missense mutation and one silent mutation. None of the BCCs showed LOH at markers flanking the SUFUH locus. Seventeen BCCs (40%) carried TP53 mutations, with only three tumours showing evidence of biallelic TP53 inactivation. TP53 mutations were present in BCCs with and without mutations in PTCH, SMOH or SUFUH. Interestingly, 72% of the TP53 alterations were presumably ultraviolet (UV)-induced transition mutations. In contrast, only 40% of the PTCH and SMOH alterations corresponded to UV signature mutations. No mutations were identified in GLI1, NRAS, KRAS, HRAS, BRAF or CTNNB1. CONCLUSIONS: Our data confirm the importance of PTCH, SMOH and TP53 mutations in the pathogenesis of sporadic BCCs. SUFUH alterations are restricted to individual cases while the other investigated genes do not appear to be important targets for mutations in BCCs.     

Congenital linear unilateral basal cell nevus: a case report with patched gene molecular studies

BACKGROUND: Linear unilateral basal cell nevus represents a linear collection of macules and papules histologically similar to basal cell carcinoma but with benign clinical behavior. We describe a patient who initially presented at the age of 6 months with a unilateral linear basal cell nevus on the right flank. The differential diagnosis included the nevoid basal cell carcinoma syndrome. Constitutional PTCH mutations are causative of the nevoid basal cell carcinoma syndrome, and somatic PTCH mutations are found in the vast majority of basal cell carcinomas. Somatic SMO mutations have also been found in some basal cell carcinomas. METHODS: Histologic examination of the lesions is performed. Short tandem-repeat molecular analysis at the PTCH locus and sequencing of PTCH and SMO genes is performed. RESULTS: Histologic examination revealed features initially indistinguishable from basal cell carcinoma. Short tandem-repeat DNA analysis did not reveal loss of heterozygosity at the PTCH locus. DNA sequencing of both the PTCH and the SMO genes from the patient's lesions revealed neither inactivating mutations of PTCH nor activating mutations of SMO. CONCLUSION: Molecular examination indicates that the PTCH and SMO genes are not involved in the pathogenesis of the patients' congenital linear unilateral basal cell nevus. Furthermore, we discuss the relationship between linear basal cell nevus and basaloid follicular hamartoma.     

Activation of expression of hedgehog target genes in basal cell carcinomas

Mutations in hedgehog signaling pathway genes, especially PTC1 and SMO, are pivotal to the development of basal cell carcinomas. The study of basal cell carcinoma gene expression not only may elucidate mechanisms by which hedgehog signaling abnormalities produce aberrant tumor cell behavior but also can provide data on in vivo hedgehog target gene control in humans. We have found, in comparison with normal skin, that basal cell carcinomas have increased levels of mRNA for PTC1, GLI1, HIP, WNT2B, and WNT5a; decreased levels of mRNA for c-MYC, c-FOS, and WNT4; and unchanged levels of mRNA for PTC2, GLI2, WNT7B, and BMP2 and 4. These findings suggest that mutations in hedgehog signaling pathway genes may exert both cell autonomous and indirect effects and indicate that basal cell carcinoma tumor cells have a phenotype that at least in some aspects resembles that of epidermal stem cells.     

Patched 1 expression in Merkel cell carcinoma

The relevance of Hedgehog signaling in Merkel cell carcinoma has only been addressed by a few studies with conflicting results. Thus, we aimed to establish the expression of Hedgehog signaling molecules in Merkel cell carcinoma to characterize causes of aberrant expression and to correlate these findings with the clinical course of the patients. Immunohistochemistry was performed for Sonic, Indian, Patched 1 (PTCH1) and Smoothened on patients’ tumor tissue. Respective mRNA expression was analyzed in 10 Merkel cell carcinoma cell lines using quantitative real‐time polymerase chain reaction. PTCH1 sequencing and DNA methylation microarray analyses were carried out on tumor tissues as well as cell lines. PTCH1 immunoreactivity in Merkel cell carcinoma was similar to that of basal cell carcinomas, which both significantly differed from PTCH1 immunoreactivity in healthy skin. Most PTCH1 mutations found were synonymous or without known functional impact. However, on average, the promoter regions of both PTCH1 were hypomethylated independently from PTCH1 gene expression or Merkel cell polyomavirus status. PTCH1 and GLI1/2/3 genes were differently expressed in different cell lines; notably, there was a significant correlation between GLI2 and PTCH1 mRNA expression. Similar to PTCH1 protein expression in patient tissues, PTCH1 gene expression in Merkel cell carcinoma cell lines is highly variable, but due to the similar methylation pattern across Merkel cell carcinoma cell lines, effects other than methylation seem to be the reason for the differential expression and PTCH1 appears to be upregulated by GLI as a classical Hedgehog target gene.     

Molekulare Grundlagen und pathogeneseorientierte Therapie epithelialer Tumoren der Haut

Basal cell carcinomas and squamous cell carcinomas are the most common human cancers and increasing in incidence. The development of novel, pathogenesis-based therapies requires a better knowledge of the molecular mechanisms leading to the development of these tumors. Basal cell carcinomas are characterized by aberrant activation of Sonic-Hedgehog (SHH) signaling due to mutations in the PTCH or SMOH genes. In addition, about 50% of the cases carry mutations in the TP53 tumor suppressor gene. Squamous cell carcinomas lack alterations of SHH signaling, while TP53 mutations are detectable in virtually all cases. Alterations in cell cycle regulatory genes, such as CDKN2A, are also common. Recently, specific inhibitors of the SHH-signaling pathway have been developed and shown promising results in preclinical studies on experimental basal cell carcinomas. However, the clinical significance of such targeted molecular therapy remains to be evaluated. Another successful pathogenesis-based therapy, which is already in clinical use, is the administration of topic immune response modifier imiquimod. This drug can eradicate non-melanoma skin cancers by different mechanisms, including cytokine-mediated stimulation of the anti-tumor immune response, as well as the induction of tumor cell apoptosis.     

Lack of evidence for activation of the hedgehog pathway in psoriasis

Recent reports have suggested that the hedgehog (Hh) pathway is activated in lesional psoriatic skin, and that treatment with the Hh pathway antagonist cyclopamine may lead to rapid resolution of the disease. To assess Hh pathway activity in psoriasis, we isolated RNA from lesional and uninvolved skin of 58 psoriatic patients, and from 63 normal control subjects, and subjected these samples to global gene expression profiling on Affymetrix HU133 Plus 2.0 gene arrays. We were especially interested in Hh target genes (PTCH1 and GLI1), whose expression is elevated in response to Hh signaling. The microarray data demonstrated downregulation of PTCH1 expression in uninvolved and lesional skin (1.1-fold and 2-fold, respectively; P<0.0001). Additionally GLI1 mRNA was downregulated in lesional skin (1.7 fold; P<0.05). No significant changes were observed between lesional and uninvolved skin for the Hh ligands or Smoothened. Quantitative PCR confirmed these findings. In situ hybridization for GLI1 and PTCH1 was positive in basal cell carcinoma tumor cells, but was negligible in uninvolved or lesional psoriatic skin. The absence of elevated Hh target gene expression in lesional psoriatic skin indicates that the Hh pathway is not activated in this disease, raising questions regarding the proposed use of Hh antagonists as antipsoriatic agents.