Integrative mRNA profiling comparing cultured primary cells with clinical samples reveals PLK1 and C20orf20 as therapeutic targets in cutaneous squamous cell carcinoma

A cutaneous squamous cell carcinoma (cSCC) derived from keratinocytes is the second most common cause of non-melanoma skin cancer. The accumulation of the mutational burden of genes and cellular DNA damage caused by the risk factors (e.g., exposure to ultraviolet radiation) contribute to the aberrant proliferation of keratinocytes and the formation of a cSCC. A cSCC encompasses a spectrum of diseases that range from recursor actinic keratosis (AK) and squamous cell carcinoma (SCC) in situ (SCCIS) to invasive cSCCs and further metastatic SCCs. Emerging evidence has revealed that lncRNAs are involved in the biological process of a cSCC. According to the ceRNA regulatory theory, lncRNAs act as natural miRNA sponges and interact with miRNA response elements, thereby regulating the mRNA expression of their down-stream targets. This study was designed to search for the potential lncRNAs that may become potential therapeutic targets or biomarkers of a cSCC. Considering the spirit of the study to be adequately justified, we collected microarray-based datasets of 19 cSCC tissues and 12 normal skin samples from the GEO database (GSE42677 and GSE45164). After screening the differentially expressed genes via a limma package, we identified 24 differentially expressed lncRNAs (DElncRNAs) and 3221 differentially expressed mRNAs (DEmRNAs). The miRcode, miRTarBase, miRDB and TargetScan databases were used to predict miRNAs that could interact with DElncRNAs and DEmRNAs. A total of 137 miRNA-lncRNA and 221 miRNA-mRNA pairs were retained in the ceRNA network, consisting of 31 miRNAs, 11 DElncRNAs and 155 DEmRNAs. For the functional analysis, the top enriched biological process was enhancer sequence-specific DNA binding in Gene Ontology (GO) terms. The FoxO signaling pathway, autophagy and cellular senescence were the top enrichment terms based on a Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The combination of a STRING tool and Cytoscape software (plug-in MCODE) identified five core mRNAs and built a core mRNA-associated ceRNA network. The expression for five identified core mRNAs and their related nine lncRNAs was validated using the external dataset GSE7553. Finally, one lncRNA HLA-F-AS1 and three mRNAs named AGO4, E2F1 and CCND1 were validated with the same expression patterns. We speculate that lncRNA HLA-F-AS1 may sponge miR-17-5p or miR-20b-5p to regulate the expression of CCND1 and E2F1 in the cSCC. The present study may provide potential diagnostic and therapeutic targets for cSCC patients.

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Tumour serine proteases C1r and C1s as novel biomarkers and therapeutic targets in invasive sporadic and recessive dystrophic epidermolysis bullosa‐associated cutaneous squamous cell carcinoma

British Journal of Dermatology ◽

10.1111/bjd.18419 ◽

2019 ◽

Vol 182 (3) ◽

pp. 530-531

Author(s):

Z. Kopecki

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Epidermolysis Bullosa ◽

Serine Proteases ◽

Therapeutic Targets ◽

Cutaneous Squamous Cell Carcinoma ◽

Dystrophic Epidermolysis Bullosa ◽

Novel Biomarkers ◽

Recessive Dystrophic Epidermolysis Bullosa

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The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

Journal of Investigative Dermatology ◽

10.1016/j.jid.2019.09.024 ◽

2020 ◽

Vol 140 (6) ◽

pp. 1154-1165.e5 ◽

Cited By ~ 2

Author(s):

Angela McHugh ◽

Kenneth Fernandes ◽

Nerime Chinner ◽

Adel F.M. Ibrahim ◽

Amit K. Garg ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Therapeutic Targets ◽

Cutaneous Squamous Cell Carcinoma

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Wnt1 and SFRP1 as potential prognostic factors and therapeutic targets in cutaneous squamous cell carcinoma

Genetics and Molecular Research ◽

10.4238/gmr.15028187 ◽

2016 ◽

Vol 15 (2) ◽

Cited By ~ 7

Author(s):

Y. Halifu ◽

J.Q. Liang ◽

X.W. Zeng ◽

Y. Ding ◽

X.Y. Zhang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Prognostic Factors ◽

Cell Carcinoma ◽

Squamous Cell ◽

Therapeutic Targets ◽

Cutaneous Squamous Cell Carcinoma

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OVOL2-Mediated ZEB1 Downregulation May Prevent Promotion of Actinic Keratosis to Cutaneous Squamous Cell Carcinoma

Journal of Clinical Medicine ◽

10.3390/jcm9030618 ◽

2020 ◽

Vol 9 (3) ◽

pp. 618 ◽

Cited By ~ 4

Author(s):

Maho Murata ◽

Takamichi Ito ◽

Yuka Tanaka ◽

Kazuhiko Yamamura ◽

Kazuhisa Furue ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Zinc Finger ◽

Squamous Cell ◽

Actinic Keratosis ◽

Cutaneous Squamous Cell Carcinoma ◽

Clinical Samples ◽

Inverse Association ◽

Mesenchymal Transition ◽

Zeb1 Expression

Progression of actinic keratosis (AK) to cutaneous squamous cell carcinoma (cSCC) is rare. Most cases of AK remain as intraepidermal lesions, owing to the suppression of the epithelial-to-mesenchymal transition (EMT). Ovo-like transcriptional repressor 1 (OVOL1) and ovo-like zinc finger 2 (OVOL2) are important modulators of EMT in some tumors, but their roles in skin tumors remain elusive. This study elucidated the roles of OVOL1/2 in AK and cSCC using 30 AK/30 cSCC clinical samples, and an A431 human SCC cell line using immunohistochemistry and molecular biological approaches. Immunohistochemically, OVOL1/2 were upregulated in AK and downregulated in cSCC. Meanwhile, EMT-related factors, vimentin and zinc finger E-box binding homeobox 1 (ZEB1) were downregulated in AK and upregulated in cSCC. Moreover, ZEB1 expression was higher in tumors in which OVOL2 expression was low. Thus, we observed an inverse association between OVOL2 and ZEB1 expression in AK and cSCC. Although knockdown of OVOL1 or OVOL2 increased the mRNA and protein levels of ZEB1, only OVOL2 knockdown increased the invasive ability of A431. In conclusion, OVOL2 inhibits ZEB1 expression and may inhibit the promotion of AK into cSCC. OVOL2/ZEB1 axis may be a potential target for preventing the development of cSCC.

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A Computational Systems Analyses to Identify Biomarkers and Mechanistic Link in Psoriasis and Cutaneous Squamous Cell Carcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.662528 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sidra Adil ◽

Rehan Zafar Paracha ◽

Salma Tariq ◽

Maryum Nisar ◽

Sadaf Ijaz ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Therapeutic Targets ◽

Cutaneous Squamous Cell Carcinoma ◽

Sequencing Data ◽

Skin Cancers ◽

Autoimmune Pathology ◽

Significant Pathway ◽

Potential Biomarkers

Psoriasis is the most common and chronic skin disease that affects individuals from every age group. The rate of psoriasis is increasing over the time in both developed and developing countries. Studies have revealed the possibility of association of psoriasis with skin cancers, particularly non-melanoma skin cancers (NMSC), which, include basal cell carcinoma and cutaneous squamous cell carcinoma (cSCC). There is a need to analyze the disease at molecular level to propose potential biomarkers and therapeutic targets in comparison to cSCC. Therefore, the second analyzed disease of this study is cSCC. It is the second most common prevalent skin cancer all over the world with the potential to metastasize and recur. There is an urge to validate the proposed biomarkers and discover new potential biomarkers as well. In order to achieve the goals and objectives of the study, microarray and RNA-sequencing data analyses were performed followed by network analysis. Afterwards, quantitative systems biology was implemented to analyze the results at a holistic level. The aim was to predict the molecular patterns that can lead psoriasis to cancer. The current study proposed potential biomarkers and therapeutic targets for psoriasis and cSCC. IL-17 signaling pathway is also identified as significant pathway in both diseases. Moreover, the current study proposed that autoimmune pathology, neutrophil recruitment, and immunity to extracellular pathogens are sensitive towards MAPKs (MAPK13 and MAPK14) and genes for AP-1 (FOSL1 and FOS). Therefore, these genes should be further studied in gene knock down based studies as they may play significant role in leading psoriasis towards cancer.

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