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      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Activation of the Hedgehog and Wnt/β-Catenin Signaling Pathways in Basal Cell Carcinoma

      case-report

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          Abstract

          In basal cell carcinoma (BCC) tumorigenesis, interaction between Hedgehog (Hh) and Wnt/β-catenin (Wnt) signaling pathways has been investigated, but not completely elucidated. Here, a case of sporadic BCC in an 80-year-old man is presented, and the effectiveness of SMO inhibitors in case of relapse is predicted. The aim of this study was to determine whether the SMO inhibitors can be effective in treating this individual should the tumor recur in the future. Immunohistochemistry (IHC) was performed in a tumor and the adjacent skin tissue from the patient. IHC within the same BCC tissue specimen revealed that Glioma-associated oncogene 1 (GLI1) and Smoothened (SMO) in the Hh signaling pathway and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in the Wnt signaling pathway were overexpressed. Hh and Wnt signaling pathways were activated. These findings suggest that the patient might be resistant to treatment with SMO inhibitors because of the interaction between Hh and Wnt signaling pathways. Overexpression of GLI1 leads to transcriptional activation, making it an attractive molecular target for anticancer therapy owing to the downstream effectors of the cascade.

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          Most cited references13

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          Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists.

          Matthias Lauth, Åsa Bergström, Takashi Shimokawa … (2007)
          The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.
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            PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations.

            Yongshuai Jiang, Ming Chen, Hong Nie … (2019)
            Programmed death-1 (PD-1) is a cell surface receptor that functions as a T cell checkpoint and plays a central role in regulating T cell exhaustion. Binding of PD-1 to its ligand, programmed death-ligand 1 (PD-L1), activates downstream signaling pathways and inhibits T cell activation. Moreover abnormally high PD-L1 expression on tumor cells and antigen-presenting cells in the tumor microenvironment mediates tumor immune escape, and the development of anti-PD-1/PD-L1 antibodies has recently become a hot topic in cancer immunotherapy. Here, we review the structure of PD-1 and PD-L1, the function of the PD-1/PD-L1 signaling pathway, the application of PD-1 or PD-L1 monoclonal antibodies and future directions for anti-PD-1/PD-L1 antibodies with combination therapies. Cancer immunotherapy using PD-1/PD-L1 immune checkpoint blockade may require more studies, and this approach may be curative for patients with many types of cancer in the future.
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              Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours.

              N Dahmane, J. Lee, P Robins … (1997)
              Sporadic basal cell carcinoma (BCC) is the most common type of malignant cancer in fair-skinned adults. Familial BCCs and a fraction of sporadic BCCs have lost the function of Patched (Ptc), a Sonic hedgehog (Shh) receptor that acts negatively on this signalling pathway. Overexpression of Shh can induce BCCs in mice. Here we show that ectopic expression of the zinc-finger transcription factor Gli1 in the embryonic frog epidermis results in the development of tumours that express endogenous Gli1. We also show that Shh and the Gli genes are normally expressed in hair follicles, and that human sporadic BCCs consistently express Gli1 but not Shh or Gli3. Because Gli1, but not Gli3, acts as a target and mediator of Shh signalling, our results suggest that expression of Gli1 in basal cells induces BCC formation. Moreover, loss of Ptc or overexpression of Shh cannot be the sole causes of Gli1 induction and sporadic BCC formation, as they do not occur consistently. Thus any mutations leading to the expression of Gli1 in basal cells are predicted to induce BCC formation.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Case Rep Dermatol
                Journal ID (iso-abbrev): Case Rep Dermatol
                Journal ID (publisher-id): CDE
                Title: Case Reports in Dermatology
                Publisher: S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
                ISSN (Electronic): 1662-6567
                Publication date Collection: Sep-Dec 2021
                Publication date (Electronic): 16 November 2021
                Publication date PMC-release: 16 November 2021
                Volume: 13
                Issue: 3
                Pages: 506-512
                Affiliations
                Sumikawa Takada Dermatology Clinic, Sapporo, Japan
                Author notes
                Article
                Publisher ID: cde-0013-0506
                DOI: 10.1159/000520256
                PMC ID: 8738910
                PubMed ID: 35082610
                SO-VID: 36085c0b-ed74-4965-bebf-1e2cccb1b114
                Copyright © Copyright © 2021 by S. Karger AG, Basel
                License:

                This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.

                History
                Date received : 12 July 2021
                Date accepted : 14 October 2021
                Date: 2021
                Page count
                Figures: 3, References: 14, Pages: 7
                Categories
                Subject: Single Case

                ScienceOpen disciplines: Dermatology
                Keywords: basal cell carcinoma,glioma-associated oncogene 1,smoothened,insulin-like growth factor 2 mrna-binding protein 1
                Data availability:
                ScienceOpen disciplines: Dermatology
                Keywords: basal cell carcinoma, glioma-associated oncogene 1, smoothened, insulin-like growth factor 2 mrna-binding protein 1

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