Development Of Cutaneous Squamous Cell Carcinoma Research Articles

MCPIP1 modulates the miRNA‒mRNA landscape in keratinocyte carcinomas

BackgroundMonocyte Chemotactic Protein 1-Induced Protein 1 (MCPIP1, also called Regnase-1) is a negative modulator of inflammation with tumor-suppressive properties. Mice with keratinocyte-specific deletion of the Zc3h12a gene, encoding MCPIP1, (Mcpip1eKO mice) are more susceptible to the development of epidermal papillomas initiated by 7,12-dimethylbenz[a]-anthracene (DMBA) and promoted by 2-O-tetradecanoylphorbol-13-acetate (TPA).MethodsThe aim of this study was to investigate the MCPIP1 RNase-dependent microRNA (miRNA)‒mRNA regulatory network in chemically induced squamous cell carcinoma (SCC)-like skin papillomas. Next-generation sequencing (NGS) coupled with bioinformatic analysis was used to shortlist the MCPIP1-dependent changes in protein-coding genes and miRNAs. The expression levels of the selected miRNAs were analyzed by quantitative PCR in human keratinocytes with MCPIP1 silencing. Functional studies were performed in human keratinocytes transfected with appropriate miRNA mimics. The DIANA-microT-CDS algorithm and DIANA-TarBase v7 database were used to predict potential target genes and identify the experimentally validated targets of differentially expressed (DE) miRNAs.ResultsRNA sequencing (RNA-Seq) analysis of control and Mcpip1eKO DMBA/TPA-induced papillomas revealed transcriptome changes, with 2400 DE protein-coding genes and 33 DE miRNAs. The expression of miR-223-3p, miR-376c-3p, and miR-139-5p was confirmed to be dependent on MCPIP1 activity in both murine and human models. We showed that MCPIP1 directly regulates the expression of miR-376c-3p via direct cleavage of the corresponding precursor miRNA. The pro-proliferative activity of miR-223-3p, miR-376c-3p, and miR-139-5p was experimentally confirmed in SCC-like keratinocytes. Bioinformatic prediction of the mRNA targets of the DE-miRNAs revealed 416 genes as putative targets of the 18 upregulated miRNAs and 425 genes as putative targets of the 15 downregulated miRNAs. Further analyses revealed the murine interactions that are conserved in humans. Functional analysis indicated that during the development of cutaneous SCC, the most important pathways/processes mediated by the miRNA‒mRNA MCPIP1-dependent network are the regulation of inflammatory processes, epithelial cell proliferation, Wnt signaling, and miRNA transcription.ConclusionsLoss of MCPIP1 modulates the expression profiles of 33 miRNAs in chemically induced Mcpip1eKO papillomas, and these changes directly affect the miRNA‒mRNA network and the modulation of pathways and processes related to carcinogenesis.

Cutaneous Squamous Cell Carcinoma in Patients with Solid-Organ-Transplant-Associated Immunosuppression.

The management of advanced cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of immunotherapy. Yet, successful treatment with immunotherapy relies on an adequate antitumor immune response. Patients who are solid-organ transplant recipients (SOTRs) have a higher incidence of CSCC compared to the general population. This review discusses the current knowledge of epidemiology, pathophysiology, and management of patients with CSCC who are immunocompromised because of their chronic exposure to immunosuppressive medications to prevent allograft rejection. First, we discuss the prognostic impact of immunosuppression in patients with CSCC. Next, we review the risk of CSCC development in immunosuppressed patients due to SOT. In addition, we provide an overview of the biological immune disruption present in transplanted immunosuppressed CSCC patients. We discuss the available evidence on the use of immunotherapy and provide a framework for the management approach with SOTRs with CSCC. Finally, we discuss potential novel approaches that are being investigated for the management of immunosuppressed patients with CSCC.

Aberrant expression of B7-H4 and B7-H5 contributes to the development of cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant tumor of the skin. B7 homolog 4 (B7-H4) and B7-H5 (B7 homolog 5) are associated with a variety of tumors. Investigate the potential role of B7-H4 and B7-H5 in regulating the tumorigenesis and progression of CSCC. B7-H4 and B7-H5 transcriptome data were collected from GEO and TCGA databases and subjected to bioinformatical analysis by protein–protein interaction (PPI) network, functional enrichment analysis, immune analysis, and drug–gene interaction prediction analysis. We characterized the expression of B7-H4 and B7-H5 in carcinoma tissues of CSCC patients by immunohistochemistry. Meanwhile, the clinical correlation of B7-H4 and B7-H5 in CSCC was explored by statistical analysis. B7-H4 and B7-H5 genes were under-expressed in CSCC and correlated with tumor staging. According to GO and KEGG Pathway enrichment analysis, B7-H4, and B7-H5 can regulate the proliferation and activation of T cells, lymphocytes, and monocytes, and the expression of cytokines, such as IL-6 and IL-10, in CSCC. B7-H4 and B7-H5 are also jointly involved in the occurrence and development of CSCC via the JAK-STAT and Notch signaling pathways. We found that B7-H4 and B7-H5 proteins were abnormally highly expressed in CSCC tissue and correlated with tumor size and stage. Our findings offer new insights into the pathogenesis of CSCC and suggest that B7-H4 and B7-H5 are novel tissue biomarkers and promising therapeutic targets for CSCC.

Stem-cell states converge in multistage cutaneous squamous cell carcinoma development.

Stem cells play a critical role in cancer development by contributing to cell heterogeneity, lineage plasticity, and drug resistance. We created gene expression networks from hundreds of mouse tissue samples (both normal and tumor) and integrated these with lineage tracing and single-cell RNA-seq, to identify convergence of cell states in premalignant tumor cells expressing markers of lineage plasticity and drug resistance. Two of these cell states representing multilineage plasticity or proliferation were inversely correlated, suggesting a mutually exclusive relationship. Treatment of carcinomas in vivo with chemotherapy repressed the proliferative state and activated multilineage plasticity whereas inhibition of differentiation repressed plasticity and potentiated responses to cell cycle inhibitors. Manipulation of this cell state transition point may provide a source of potential combinatorial targets for cancer therapy.

Tracing human papillomavirus in skin and mucosal squamous cell carcinoma: a histopathological retrospective survey.

Worldwide, squamous cell carcinoma (SCC) incidence is rising. The literature debates the human papillomavirus (HPV)'s role in cutaneous SCC development. We examined HPV histopathology in SCC samples in this study. Retrospective study at tertiary referral skin center in 2020. Histopathological features of HPV, including koilocytosis, hyperkeratosis, acanthosis, hypergranulosis, parakeratosis, solar elastosis, papillomatosis, and tumor grade, were examined in SCC specimens. Two dermatopathologists independently reevaluated all samples. We examined 331 SCC cases (male:female ratio = 3.9:1). The mean age was 68.1, with 15.1 standard deviation. Lesions were most common on the face (40.5%), scalp (22.7%), and extremities (20.8%). Koilocytes were found in 50 (15.1%) lesions. Nail (38.1%, p=0.007), oral cavity (36.8%, p=0.014), and genitalia (60.0%, p=0.026) lesions had higher koilocytosis rates. SCCs were found in 6.6% of specimens, but in situ tumors had the highest koilocytosis (64.7%), significantly higher than other grades (p<0.001). SCC pathology often shows HPV and specific koilocyte histopathology. Well-differentiated SCC has a stronger association with nail, oral, and genital lesions.

Radix Tetrastigma Hemsleyani Flavone represses cutaneous squamous cell carcinoma via Janus kinase/signal transducer and activator of transcription 3 pathway inactivation

Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant skin tumor and significantly affects patients’ quality of life and health. The Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway activation is involved in CSCC development. Radix Tetrastigma hemsleyani flavone (RTHF) is an active Radix Tetrastigma extract (RTE), which was recently reported to have promising inhibitory effects on CSCC. However, the underlying functional mechanisms of this inhibition remain unknown. In the present study, A431 cells or SCL-1 cells were incubated with 1, 5, and 10 mg/mL RTHF for 48 h, respectively. A significantly increased wound closure rate, decreased number of migrated and invaded cells, decreased colony number, and elevated apoptotic rate were observed after treatment with 1, 5, and 10 mg/mL RTHF. Furthermore, after incubation with RTHF, p-JAK1/JAK1, p-JAK2/JAK2, and p-STAT3/STAT3 levels were drastically reduced. An A431 xenograft model was constructed, followed by oral administration of 15, 30, or 60 mg/kg RTHF for 21 consecutive days. A significantly lower increase in tumor volume and reduced tumor weight were observed in all RTHF-treated groups. In addition, JAK/STAT3 signaling was drastically repressed in tumor tissues. Collectively, RTHF inhibited CSCC progression, which may be associated with JAK/STAT3 pathway inactivation.

Hsa_circ_0005085 may suppress cutaneous squamous cell carcinoma growth and metastasis through targeting the miR-186-5p/LAMC1 axis.

Cutaneous squamous cell carcinoma (CSCC) is asevere malignancy derived from the skin. Mounting evidence suggests that circular RNAs (circRNAs) participate in diverse biological functions in human cancers, containing CSCC. However, the biological functions and underlyingmechanism of hsa_circ_0005085 in CSCC have not been clearly studied. Expression levels of hsa_circ_0005085, microRNA-186-5p (miR-186-5p), and Laminin subunit gamma 1 (LAMC1) were detected by reverse transcription-quantitative polymerase chain reaction. Cell counting kit-8 assay, colony formation assay, and 5-Ethynyl-2'-deoxyuridine assay were used to assess cell proliferation. Transwell assay was conducted to detect cell migration and invasion. Cell apoptosis was analyzed by flow cytometry. Protein expression of LAMC1, E-cadherin, Snail, and slug were assessed using western blot assay. Using bioinformatics software, the binding between miR-186-5p and hsa_circ_0005085 or LAMC1 was predicted, followed by verification using a dual-luciferase reporter and RNA-Immunoprecipitation. The mouse xenograft model was established to investigate the role of hsa_circ_0005085 in vivo. Hsa_circ_0005085 level was downregulated in CSCC tissues and cells. Overexpression of hsa_circ_0005085 inhibited cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and promoted cell apoptosis in CSCC. MiR-186-5p could restore the effect of hsa_circ_0005085 overexpression on CSCC cells, and the knockdown of LAMC1 reversed the regulation of the miR-186-5p inhibitor. In mechanism, hsa_circ_0005085 served as a sponge for miR-186-5p to regulate LAMC1 expression. Overexpression of hsa_circ_0005085 reduced growth of tumor via miR-186-5p/LAMC1 axis in vivo. In our study, hsa_circ_0005085 might inhibit CSCC development by targeting the miR-186-5p/LAMC1 axis, which might provide a promising therapeutic target for CSCC.

Host and primary tumor factors for the development of multiple cutaneous squamous cell carcinomas among a retrospective cohort in Rhode Island

Risk factors for a primary cutaneous squamous cell carcinoma (CSCC) are well-established; however, the host and primary tumor risk factors for subsequent CSCC have not been fully explored. We performed a retrospective chart review of patients diagnosed with CSCC in an academic dermatology clinic in Rhode Island from 2016-2019. Logistic regression was used to evaluate the associations between host factors and multiple CSCC and between primary tumor characteristics and the risk of subsequent CSCC. Adjusted odds ratios (aORs) and 95% CIs were calculated. A total of 1312 patients with CSCC diagnoses were included. Host risk factors significantly associated with multiple CSCCs included: aged >80years (aOR, 2.18; 95% CI, 1.46-3.31); history of: solid organ transplant (aOR, 2.41; 95% CI, 1.20-4.80); skin cancer (aOR, 1.96; 95% CI, 1.52-2.54); other cancer (aOR, 1.49; 95% CI, 1.11-2.00); family history of skin cancer (aOR, 1.36; 95% CI, 1.03-1.78); and actinic keratosis (aOR, 1.52; 95% CI, 1.18-1.95). Tumor location, diameter, histologic differentiation, and treatment were not significant predictors of subsequent CSCCs. Study patients were predominantly White and from a single institution, limiting the generalizability of results. Certain host characteristics were associated with the development of subsequent CSCC, which may inform clinical guidelines for follow-up.

The Role of NFATC4 Gene in Human Cutaneous Squamous Cell Carcinoma.

Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4) has been implicated in keratinocyte development and several types of cancer. A well-defined role for NFATC4 in cutaneous squamous cell carcinoma (CSCC) has not yet been established. In this study, NFATC4 gene function in CSCC development was examined. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to measure the mRNA expression of NFATC4 in CSCC tissues and controls. A431 and Colo16 cell proliferation, invasion, and apoptosis were measured by CCK-8 assay, transwell invasion, and flow cytometry, respectively, after an NFATC4 expression lentivirus infection. Animal models were applied to validate the function of the NFATC4 gene. (1) CSCC tissues showed a significant decrease in NFATC4 expression compared to controls. (2) Overexpression of NFATc4 suppresses A431 and Colo16 cell proliferation and invasion but promotes cell apoptosis. (3) Mouse models overexpressing NFATC4 showed reduced tumourigenesis. It was suggested that NFATC4 might be a tumour suppressor gene in CSCC.

34405 Host and primary tumor factors for the development of multiple cutaneous squamous cell carcinomas

Introduction: Risk factors for the development of a primary cutaneous squamous cell carcinoma (CSCC) are well-established, but risk factors for subsequent CSCCs are not. While history of prior CSCC is considered the single strongest predictor for development of subsequent CSCCs, the host and primary tumor risk factors at play have not been fully explored.

Risk of squamous cell carcinoma in immunosuppressed patients with voriconazole-related actinic keratosis.

Voriconazole is commonly administered for a long period to patients receiving immunosuppressive therapy. Although voriconazole potentially induces skin cancers in association with sun exposure, this has not yet been examined in detail in a single ethnic patient group. Therefore, the present study investigated the risk of developing squamous cell carcinoma (SCC) in Japanese patients with voriconazole-related actinic keratosis (AK) and the prognosis of Japanese patients with voriconazole-related SCC. We retrospectively examined 37 Japanese patients with AK, including five voriconazole-treated patients (mean age, 57.9 ± 16.3years) and 32 non-treated patients (74.9 ± 9.2years), and 18 Japanese patients with SCC, including four voriconazole-treated patients (55.4 ± 16.7years) and 14 non-treated patients (74.1 ± 10.7years). Among the 37 patients with AK, SCC developed in five, including four with a history of treatment with both voriconazole and immunosuppressive agents, independent of AK progression. In these four patients, the mean period from the diagnosis of AK to that of SCC was 13.8 ± 11.6months. Kaplan--Meier analyses showed that the risk of developing SCC was significantly higher in patients with both voriconazole and immunosuppressants/corticosteroid-treated patients with AK than in non-voriconazole-treated patients with AK (the Log-rank test, p < 0.001). The analyses also showed that the mortality rate was significantly higher in patients with both voriconazole and immunosuppressants/corticosteroid-treated patients with SCC than in non-voriconazole-treated patients with SCC (p=0.018). The present results suggest that voriconazole-related AK precedes the development of cutaneous SCC and voriconazole-related SCC leads to a poor prognosis under the immunosuppressive condition.

LncRNA NEAT1 Targets miR-342-3p/CUL4B to Inhibit the Proliferation of Cutaneous Squamous Cell Carcinoma Cells.

Objective This study investigated whether lncRNA NEAT1 could inhibit the proliferation of cutaneous squamous cell carcinoma (CSCC) cells by targeting miR-342-3p/CUL4B, thereby affecting the occurrence and development of CSCC. Methods Fluorescence quantitative PCR was used to detect the expression of lncRNA NEAT1 and miR-42-3p in skin squamous cell carcinoma and adjacent tissues. Bioinformatics software and luciferase reporter gene assay were used to analyze the association of lncRNA NEAT1 and miR-342-3p. The effect of overexpression or knockdown of miR-342-3p on the proliferation of CSCC cells was examined by MTT and colony formation assays. Western blotting was used to detect the proteins of the miR-342-3p/CUL4B signaling axis. Results The lncRNA NEAT1 is abnormally overexpressed in CSCC tissues and cell lines. The expression of lncRNA NEAT1 and miR-342-3p in CSCC was negatively correlated. Bioinformatics prediction analysis revealed that lncRNA NEAT1 regulates the expression of miR-342-3p. The results of MTT and plate colony formation experiments showed that the transfection of miR-342-3p mimics significantly inhibited the proliferation and plate colony formation of CSCC cells, while the transfection of miR-342-3p inhibitor significantly promoted the proliferation and plate colony-forming ability of CSCC cells. Western blot results showed that lncRNA NEAT1 affected CSCC cell proliferation through miR-342-3p/CUL4B/PI3K-Akt signaling pathway. Conclusion The expression of lncRNA NEAT1 and miR-342-3p in CSCC tissues was negatively correlated. This study is the first to demonstrate that the lncRNA NEAT1, as a ceRNA, affects the proliferation of skin squamous cell carcinoma cells through the miR-342-3p/CUL4B/PI3K-Akt signaling pathway. Therefore, lncRNA NEAT1 could be a biological marker or target for CSCC diagnosis or treatment.

The Aryl Hydrocarbon Receptor in the Pathogenesis of Environmentally-Induced Squamous Cell Carcinomas of the Skin.

Cutaneous squamous cell carcinoma (SCC) is one of the most frequent malignancies in humans and academia as well as public authorities expect a further increase of its incidence in the next years. The major risk factor for the development of SCC of the general population is the repeated and unprotected exposure to ultraviolet (UV) radiation. Another important risk factor, in particular with regards to occupational settings, is the chronic exposure to polycyclic aromatic hydrocarbons (PAH) which are formed during incomplete combustion of organic material and thus can be found in coal tar, creosote, bitumen and related working materials. Importantly, both exposomal factors unleash their carcinogenic potential, at least to some extent, by activating the aryl hydrocarbon receptor (AHR). The AHR is a ligand-dependent transcription factor and key regulator in xenobiotic metabolism and immunity. The AHR is expressed in all cutaneous cell-types investigated so far and maintains skin integrity. We and others have reported that in response to a chronic exposure to environmental stressors, in particular UV radiation and PAHs, an activation of AHR and downstream signaling pathways critically contributes to the development of SCC. Here, we summarize the current knowledge about AHR’s role in skin carcinogenesis and focus on its impact on defense mechanisms, such as DNA repair, apoptosis and anti-tumor immune responses. In addition, we discuss the possible consequences of a simultaneous exposure to different AHR-stimulating environmental factors for the development of cutaneous SCC.

Research on Correlations of miR-196a Expression with Progression and Prognosis of Cutaneous Squamous Cell Carcinoma.

PurposeThis study aimed to investigate the correlation between miR-196a expression and the progression and prognosis of cutaneous squamous cell carcinoma (CSCC).Patients and MethodsTissue samples and corresponding paracancerous tissue samples from 117 patients with CSCC were collected. The qRT-PCR analysis was used to detect the expression levels of miR-196a. Kaplan–Meier curve and Cox regression analyses were used to analyze the relationship between miR-196a expression and patients’ prognosis. The CCK-8 and transwell assays were used to explore the effects of miR-196a on the abilities of cell proliferation, migration, or invasion.ResultsmiR-196a expression was significantly up-regulated in CSCC tissues or cell lines, compared with adjacent normal tissues or cell lines, respectively. High expression of miR-196a was associated with positive lymph node metastasis, high TNM stages, and a lower five-year survival rate. The expression level of miR-196a was up-regulated and the proliferation, migration or invasion ability of cells were significantly increased accordingly.ConclusionmiR-196a is highly expressed in CSCC, thus affecting the occurrence and development of CSCC. More importantly, miR-196a was shown to have potential as a prognostic marker for CSCC.

Integrated tissue proteome and metabolome reveal key elements and regulatory pathways in cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (CSCC) is a widespread malignancy but has a very low long-term survival rate for patients at the metastatic stage. Therefore, it is urgent to identify prognostic biomarkers for CSCC and improve our understanding of disease progression. Here we took advantage of a data-independent acquisition (DIA)-based nano liquid chromatography equipped with an orbitrap mass spectrometry (nLC-MS/MS) and ultraperformance LC coupled to a time-of-flight tandem MS (UPLC-TOF-MS/MS) technique to analyze cancer and corresponding noncancerous tissues from 20 CSCC patients for integrated proteomic and metabolomic analyses. Overall, 6241 tissue proteins were detected, while 136 proteins were significantly expressed in CSCC tissues. Further functional analysis revealed that various biological processes were highly enriched and participated in the pathogenesis of CSCC, especially DNA damage responses. Moreover, 641 named metabolites in total were identified, among which 181 were significantly changed in CSCC tissues. A total of 101 pathways were significantly enriched including apoptosis, autophagy, PI3K-Akt and mTOR signaling pathways. Interestingly, two pathways, protein digestion & absorption and platelet activation were both enriched in proteomic and metabolomic studies involving 5 proteins and 11 metabolites. Accordingly, a four-metabolite panel consisting of arachidonate, glutamine, glutamic acid, and proline (all area under the curve (AUC) values more than 0.9) was developed with a high accuracy (0.971) to distinguish the 20 detected cancer tissues from their noncancerous tissues. Collectively, our work highlighted the key elements and regulatory pathways involved in the pathogenesis of CSCC. More importantly, the present study not only provided potential biomarkers for the early diagnosis of CSCC, but also expanded our knowledge of the physiopathology of the disease. SignificanceCSCC is the second most common human cancer but has few treatment options and few sensitive biomarkers for diagnosis. Here we comprehensively revealed its molecular characteristics by performing integrated tissue proteomic and metabolomic analyses. Significantly distinct profiles and certain enriched pathways including DNA damage responses were identified as associated with CSCC. Moreover, protein digestion & absorption and platelet activation were both enriched in the proteome and metabolome. These identified molecular changes probably play significant roles in CSCC development. Finally, we developed a four-metabolite panel to distinguish CSCC with high accuracy. Overall, our data not only provided potential diagnostic biomarkers, but also extended knowledge on the pathogenesis of CSCC.

Decreased TMEM40 expression is associated with malignant behavior of cutaneous squamous cell carcinoma and inhibits tumor progression.

Cutaneous squamous cell carcinoma (CSCC) is one of the most common types of skin cancer in humans worldwide. The identification and characterization of cancer-associated transmembrane proteins are important for understanding the molecular biology of CSCC. The aim of the present study was to evaluate the expression pattern of transmembrane protein 40 (TMEM40) in CSCC and its clinical significance. The underlying mechanisms were also examined. Reverse transcription-quantitative PCR, western blot and immunohistochemistry analysis were used to determine the relative expression of TMEM40 in CSCC cell lines and clinical tissue samples. The effect of TMEM40 gene silencing on cell proliferation was also evaluated using Cell Counting Kit-8 assays. Wound healing assays, flow cytometry and Transwell assays were used to explore the migration, cell cycle distribution/apoptosis and invasion of CSCC cells following TMEM40 silencing, respectively. In the present study, increased TMEM40 expression was observed in CSCC tissue samples, compared with normal skin, and TMEM40 expression was associated with large tumor size in patients with CSCC. In vitro functional assays indicated that TMEM40 was involved in the regulation of A431 and SCL1 cell growth through its effects on the cell cycle and apoptosis. Silencing TMEM40 in A431 and SCL1 cells resulted in cell cycle arrest at the G0/G1 phase and promoted apoptosis. In addition, migration and invasion were significantly inhibited following silencing of TMEM40 expression in CSCC cells. Taken together, the results of the present study indicated that reduced TMEM40 expression could inhibit CSCC development and that TMEM40 may represent a therapeutic target in CSCC.

Actual treatment options for locally advanced and metastatic cutaneous squamous cell carcinoma

Squamous cell carcinoma of the skin, or cutaneous squamous cell carcinoma (CSCC), is the second most frequent type of skin cancer, and its incidence continues to rise all over the world. Usually has a benign clinical behavior, but it can be presented as locally invasive and metastatic aggressive tumor with 2% mortality rate. Nowadays, new risk factors for have appeared, that form pharmacologically-induced CSCC after immunosuppressant drugs used for organ transplantation, or BRAF inhibitors used for melanoma. In recent years we have got a new information about the role of mutational burden, signaling pathways involved in CSCC development and new possibilities and molecules for targeted therapy. Better understanding of the immune system functioning and benefits of immunotherapy with immune checkpoint inhibitors (PD-1) for CSCC that has changed the therapeutic approach. According to recent clinical trials data, new treatment options with PD-1 inhibitors achieved a response rate of 50% for locally advanced CSCC and 47% for metastatic CSCC, including 16.1% complete remissions. This review focuses on the molecular profile, targeted therapies and immunotherapy for locally advanced and metastatic CSCC.

Cutaneous Squamous Cell Carcinoma Development Is Associated with a Temporal Infiltration of ILC1 and NK Cells with Immune Dysfunctions

NK cells and tissue-resident innate lymphoid cells (ILCs) are innate effectors found in the skin. To investigate their temporal dynamics and specific functions throughout the development of cutaneous squamous cell carcinoma (cSCC), we combined transcriptomic and immunophenotyping analyses in mouse and human cSCCs. We identified an infiltration of NK cells and ILC1s as well as the presence of a few ILC3s. Adoptive transfer of NK cells in NK cell‒ and ILC-deficient Nfil3-/- mice revealed a role for NK cells in early control of cSCC. During tumor progression, we identified a population skewing with the infiltration of atypical ILC1 secreting inflammatory cytokines but reduced levels of IFN-γ at the papilloma stage. NK cells and ILC1s were functionally impaired, with reduced cytotoxicity and IFN-γ secretion associated with the downregulation of activating receptors. They also showed a high degree of heterogeneity in mouse and human cSCCs with the expression of several markers of exhaustion, including TIGIT on NK cells and PD-1 and TIM-3 on ILC1s. Our data show an enrichment in inflammatory ILC1 at the precancerous stage together with impaired antitumor functions in NK cells and ILC1 that could contribute to the development of cSCC and thus suggest that future immunotherapies should take both ILC populations into account.

CircRNA circ_0067772 aggravates the malignant progression of cutaneous squamous cell carcinoma by regulating miR-1238-3p/FOXG1 axis.

Cutaneous squamous cell carcinoma (CSCC) is a severe malignancy derived from skin. Dysregulated circular RNAs (circRNAs) might play vital roles in tumor development. Here, we aimed to explore the function of a novel circRNA circ_0067772 in CSCC. Quantitative real-time PCR (qRT-PCR) or Western blot assay was performed to determine the expression of circ_0067772, microRNA (miR)-1238-3p and forkhead box protein G1 (FOXG1). Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8) assay and colony formation assay. Transwell assay and wound healing assay were employed to examine cell metastasis. Flow cytometry was employed to monitor cell cycle and apoptosis. The target association between miR-1238-3p and circ_0067772 or FOXG1 was validated by dual-luciferase reporter assay. Moreover, role of circ_0067772 in vivo was investigated via xenograft model in nude mice. Circ_0067772 and FOXG1 were upregulated, while miR-1238-3p was downregulated in CSCC tissues and cells. Circ_0067772 knockdown conferred inhibitory effects on cell proliferation, migration and invasion of CSCC cells. MiR-1238-3p served as a target of circ_0067772, whose silencing could reverse circ_0067772 knockdown-induced inhibitory impact on the malignant cellular behaviors. Circ_0067772 positively regulated FOXG1 expression by antagonizing miR-1238-3p. Additionally, miR-1238-3p could repress CSCC cell proliferation, migration and invasion by targeting FOXG1. Also, circ_0067772 knockdown hindered CSCC tumor growth in vivo. Our study identified a novel oncogenic circRNA and the involvement of circ_0067772/miR-1238-3p/FOXG1 axis in CSCC development, providing a target for CSCC therapy.

A Systematic Review and Meta-Analysis: Evaluation of the β-Human Papillomavirus in Immunosuppressed Individuals with Cutaneous Squamous Cell Carcinoma.

BackgroundSome types of beta-human papillomavirus (β-HPV) may be one of the probable causes of squamous cell carcinoma (SCC) in transplant recipients. β-HPVs are linked to SCC in the literature with small number of subjects.AimHerein, the first meta-analysis was carried out on the association between β-HPVs and cutaneous SCC in immunosuppressed patients.MethodsA systematic search was carried out in the PubMed and Scopus databases up to December 2018. The odds ratio (OR) were calculated by RevMan 5.3 software and the event rate (ER) by Comprehensive Meta-Analysis 2.0 software with a 95% confidence interval (CI).ResultsA total of 1250 records were identified through the two databases, but at last eleven studies were included in the meta-analysis that they were published from 1989 to 2018. The results showed a significantly high prevalence of β-HPVs in cutaneous SCC patients (ER = 69.1%; 95%CI: 58.7%, 77.8%). In addition, the prevalence of overall β-HPVs and β-HPVs of 5, 8, 9, 17, 49, 75, and 76 in immunosuppressed cutaneous SCC patients was significantly higher compared with controls.ConclusionsThe findings of the present meta-analysis support the hypothesis that β-HPV may play a role in cutaneous SCC development in immunosuppressed individuals.