Cutaneous Squamous Cell Carcinoma Research Articles

The Role of Health Literacy in Skin Cancer Preventative Behavior and Implications for Intervention: A Systematic Review.

Health literacy is essential for individuals to access, understand, and utilize information and services to inform health related decisions and actions. As one of the most diagnosed and preventable forms of cancer, skin cancer disease risk can be reduced through preventative behavior. Currently, there is no focused study looking specifically at health literacy and skin cancer. An understanding of how health literacy affects skin cancer-related preventive behaviors can improve current practices in skin cancer prevention. To systematically identify, synthesize, and summarize findings on the role of health literacy in skin cancers (including cutaneous squamous cell carcinoma, basal cell carcinoma, and melanoma), with a focus on preventive behaviors using studiesthat utilized quantifiablehealth literacy measurements. A literature search was performed by searching PubMed, Embase, PsycINFO, and CINAHL from inception until September 26, 2023 to identify cross-sectional, case-control, cohort, or randomized controlled studies that investigated the association between health literacy and skin cancer prevention and diagnosis. Health literacy levels varied across geographic regions, specific populations, and ethnicities. Most of the included studies found a positive association between higher health literacy and better skin cancer preventative behaviors. This included sun-protective behaviors such as: wearing sleeved shirts or shirts with collars, using gloves, covering head and face, limiting sun exposure, more sunscreen use, and less sunbathing or indoor tanning. Higher health literacy was associated with increased likelihood to engage in genetic testing and less family influence on health in one study which assessed determinants of interest in skin cancer genetic testing. Another study investigating family communication about skin cancer found that higher health literacy was associated with increased family communication regarding general cancer risk. One sun protection interventional education program was effective at increasing participants' knowledge, awareness of skin cancer risk, willingness to change sun protection, and use of sun protection, but results varied between ethnic groups. Skin cancer-related educational interventions can be effective in improving health literacy and potentially lessen the impact of skin cancer through positive behavior modification, early detection, and disease knowledge and awareness. Interventions need to be tailored to its target population to maximize effectiveness due to thevarying baseline of health literacy identified across different geographic and ethnic groups. Protocol Registration PROSPERO CRD42022340826.

Management Approaches for High-Risk Cutaneous Squamous Cell Carcinoma with Perineural Invasion: An Updated Review.

Cutaneous squamous cell carcinoma (cSCC) stands as the second most prevalent non-melanoma skin cancer worldwide, comprising approximately 20% of all cutaneous malignancies. Determining its precise incidence poses challenges; however, reports indicate a global increase in its prevalence. At the time of diagnosis, the majority of cSCCs are localized, resulting in favorable 5-year cure rates surpassing 90%. Nevertheless, a subset of patients (3-7%) encounters locally advanced or metastatic cSCC, leading to substantial morbidity and mortality. The risk of metastasis ranges from 0.1% to 9.9%, carrying an associated mortality risk of 2.8%. Factors influencing recurrence, metastasis, and disease-specific mortality underscore the significance of perineural invasion (PNI) as a key indicator. Patients with PNI may manifest clinical symptoms and/or radiologic signs of PNI, while the majority remain asymptomatic, and PNI is frequently identified upon histologic examination. Despite its lower frequency compared to other cancer types, PNI serves as a recognized adverse prognostic factor for cSCC. Surgery is the elective treatment for these patients, while the role of adjuvant radiotherapy (ART) is yet contentious and have not been conclusively assessed, particularly in clear surgical margin. Prospective comparative studies are required to comprehensively evaluate the benefit and the risks of ART for cSCC and PNI patients.

Micro RNA Dysregulation in Keratinocyte Carcinomas: Clinical Evidence, Functional Impact, and Future Directions

The keratinocyte carcinomas, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC), are the most common cancers in humans. Recently, an increasing body of literature has investigated the role of miRNAs in keratinocyte carcinoma pathogenesis, progression and their use as therapeutic agents and targets, or biomarkers. However, there is very little consistency in the literature regarding the identity of and/or role of individual miRNAs in cSCC (and to a lesser extent BCC) biology. miRNA analyses that combine clinical evidence with experimental elucidation of targets and functional impact provide far more compelling evidence than studies purely based on clinical findings or bioinformatic analyses. In this study, we review the clinical evidence associated with miRNA dysregulation in KCs, assessing the quality of validation evidence provided, identify gaps, and provide recommendations for future studies based on relevant studies that investigated miRNA levels in human cSCC and BCC. Furthermore, we demonstrate how miRNAs contribute to the regulation of a diverse network of cellular functions, and that large-scale changes in tumor cell biology can be attributed to miRNA dysregulation. We highlight the need for further studies investigating the role of miRNAs as communicators between different cell types in the tumor microenvironment. Finally, we explore the clinical benefits of miRNAs as biomarkers of keratinocyte carcinoma prognosis and treatment.

Differential expression analysis of cutaneous squamous cell carcinoma and basal cell carcinoma proteomic profiles sampled with e-biopsy

Clinical misdiagnosis between cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) affects treatment plans. We report a tissue sampling approach with molecular biopsy using electroporation. This method, coined e-biopsy, enables non-destructive non-thermal permeabilization of cells in the skin for vacuum-assisted extraction of biomolecules. We used e-biopsy for ex vivo proteome extraction from 3 locations per patient in 21 cSCC, 20 BCC and 7 actinic keratosis human skin samples. Using liquid chromatography mass spectrometry (LC/MS/MS), we identified 5,966 proteins observed with non-zero intensity in at least one samples. The intra-patient Pearson correlation of 0.888 ± 0.065 for BCC patients; 0.858 ± 0.077 for SCC patients; 0.876 ± 0.116 for solar actinic keratosis (AK) patients indicates high consistency of the e-biopsy sampling. The mass spectra presented significantly different proteome profiles for cSCC, BCC and AK, with several hundreds of proteins differentially expressed. Notably, our study showed that proteomes sampled with e-biopsy from cSCC and BCC lesions are different, and that proteins of CRNN, SULT1E1 and ITPK1 genes are significantly overexpressed in BCC in comparison to cSCC. Our results provide evidence that the e-biopsy approach could potentially be used as a tool to support cutaneous lesions classification with molecular pathology.

Impact of the COVID-19 pandemic on international cutaneous squamous cell carcinoma incidence: A systematic review and meta-analysis.

Non-melanoma skin cancer (NMSC) is the most common cancer globally in white ethinicity populations, and cutaneous squamous cell carcinoma (cSCC) is the second most common subtype. The COVID-19 pandemic severely impacted public and private healthcare systems. Many studies have reported reduced cancer diagnoses during the pandemic. The impact of the COVID-19 pandemic on global cSCC and NMSC incidence is poorly reported. The aim was to conduct a systematic review and meta-analysis to assess the impact of the COVID-19 pandemic on global cSCC and NMSC incidence rates, compared with 2019 incidence rates. Two primary outcome measures were used: crude incidence rate ratios (CIRR) and age-standardised incidence rate ratios (ASIRR). A structured search was undertaken on 23 March 2023 using grey literature and four electronic databases: MEDLINE, CINAHL, EMBASE and Web of Science. Studies published before January 2020 were excluded. A quality assessment was undertaken using A. Lomas quality assessment tool. CIRR outcomes were synthesised in a meta-analysis, while ASIRR outcomes were narratively synthesised. Fourteen cancer registries were included, capturing data from 13 countries across Europe. Variation was observed in NMSC and cSCC incidence across the cancer registries. Pooled cSCC crude incidence rates in 2020 were equal to crude incidence rates in 2019 (cSCC-CIRR 1.00 (95% confidence interval (CI) 0.94-1.06). In 2021, the pooled result indicated a non-significant 8% increase in cSCC crude incidence rates, compared with 2019 (cSCC-CIRR 1.08 (95% CI 0.98-1.19). Significant reductions were reported in NMSC incidence across all meta-analyses in 2020 and 2021 compared with 2019. Heterogeneity was observed across most pooled estimates (I 2>75%). There was a lack of high quality data on cSCC incidence rates recorded during the pandemic outside of Europe. The COVID-19 pandemic resulted in no significant changes in cSCC incidence across Europe. By contrast, NMSC incidence fell across Europe following the pandemic. Significant reductions in pooled NMSC incidence rates may reflect a delay in basal cell carcinoma presentation, diagnosis and treatment. Although annual incidence rates for cSCC were not affected by the pandemic, delays in treatment may still have occurred, which may result in poorer outcomes yet to be fully understood.

Targeting PAK1 is effective against cutaneous squamous cell carcinoma in a syngenic mouse model.

By taking advantage of forward genetic analysis in mice, we have demonstrated that Pak1 plays a crucial role during DMBA/TPA skin carcinogenesis. Although Pak1 has been considered to promote cancer development, its overall function remains poorly understood. To clarify the functional significance of Pak1 in detail, we sought to evaluate the possible effect of an allosteric inhibitor against PAK1 (NVS-PAK1-1) on a syngeneic mouse model. To this end, we established two cell lines, 9AS1 and 19AS1, derived from DMBA/TPA-induced squamous cell carcinoma (SCC) that engrafted in FVB mice. Based on our present results, NVS-PAK1-1 treatment significantly inhibited the growth of tumors derived from 9AS1 and 19AS1 cells invitro and invivo. RNA-sequencing analysis on the engrafted tumors indicates that NVS-PAK1-1 markedly potentiates the epidermal cell differentiation and enhances the immune response in the engrafted tumors. Consistent with these observations, we found an expansion of Pan-keratin-positive regions and potentially elevated infiltration of CD8-positive immune cells in NVS-PAK1-1-treated tumors as examined by immunohistochemical analyses. Together, our present findings strongly suggest that PAK1 is tightly linked to the development of SCC, and that its inhibition is a promising therapeutic strategy against SCC.

Prevention of supercritical carbon dioxide fluid extract from Chrysanthemum indicum Linnén on cutaneous squamous cell carcinomas progression following UV irradiation in mice.

Chrysanthemum indicum Linnén (C. indicum), a medicinal and food herb with various bioactive components, may be of beneficial use in cosmetics and the treatment of skin-related diseases. However, to date, few studies have been reported on its potential preventive and therapeutic effects on skin cancer. Therefore, the present study aimed to investigate the effect and potential mechanism of action of supercritical carbon dioxide extract from C. indicum (CISCFE) on UV-induced skin cancer in a mouse model. Kunming mice were allocated randomly to five treatment groups: Sham, model, low concentration CISCFE, high concentration CISCFE and positive control nicotinamide groups. The dorsal skin of mice was irradiated with UV light for 31 weeks. Histopathological changes, ELISA assays, immunohistochemical analysis and western blotting were performed to investigate the potential therapeutic effects of CISCFE. The results showed that CISCFE alleviated skin oxidative and inflammatory damage in a UV-induced mouse model of skin cancer. Moreover, CISCFE suppressed abnormal activation of proto-oncogene c-Myc and the overexpression of Ki-67 and VEGF, and increased expression of the anti-oncogene PTEN, thereby reducing abnormal proliferation of the epidermis and blood vessels. Additionally, CISCFE increased the protein expression levels of NAD-dependent protein deacetylase sirtuin-1 (SIRT1), Kelch-like ECH associated protein 1 (Keap1) and inhibited the expression of nuclear factor 2 erythroid 2-related factor 2 (Nrf2), phosphorylated (p)-p62 (Ser 349), p-p65 and acetyl-p65 proteins in a UV-induced skin cancer mouse model. In summary, CISCFE exhibited potent anti-skin cancer activity, which may be attributed its potential effects on the p62/Keap1-Nrf2 and SIRT1/NF-κB pathways.

IGF1R signaling induces epithelial-mesenchymal plasticity via ITGAV in cutaneous carcinoma

BackgroundEarly cutaneous squamous cell carcinomas (cSCCs) generally show epithelial differentiation features and good prognosis, whereas advanced cSCCs present mesenchymal traits associated with tumor relapse, metastasis, and poor survival. Currently, the mechanisms involved in cSCC progression are unclear, and the established markers are suboptimal for accurately predicting the clinical course of the disease.MethodsUsing a mouse model of cSCC progression, expression microarray analysis, immunofluorescence and flow cytometry assays, we have identified a prognostic biomarker of tumor relapse, which has been evaluated in a cohort of cSCC patient samples. Phosphoproteomic analysis have revealed signaling pathways induced in epithelial plastic cancer cells that promote epithelial-mesenchymal plasticity (EMP) and tumor progression. These pathways have been validated by genetic and pharmacological inhibition assays.ResultsWe show that the emergence of epithelial cancer cells expressing integrin αV (ITGAV) promotes cSCC progression to a mesenchymal state. Consistently, ITGAV expression allows the identification of patients at risk of cSCC relapse above the currently employed clinical histopathological parameters. We also demonstrate that activation of insulin-like growth factor-1 receptor (IGF1R) pathway in epithelial cancer cells is necessary to induce EMP and mesenchymal state acquisition in response to tumor microenvironment-derived factors, while promoting ITGAV expression. Likewise, ITGAV knockdown in epithelial plastic cancer cells also blocks EMP acquisition, generating epithelial tumors.ConclusionsOur results demonstrate that ITGAV is a prognostic biomarker of relapse in cSCCs that would allow improved patient stratification. ITGAV also collaborates with IGF1R to induce EMP in epithelial cancer cells and promotes cSCC progression, revealing a potential therapeutic strategy to block the generation of advanced mesenchymal cSCCs.Graphical During cSCC progression, cancer cells evolve from the epithelial to the mesenchymal state, which is associated with poor prognosis. The current investigation reveals that, at intermediate cSCC stages (MD/PD-SCC), epithelial cancer cells activate IGF1R and ITGAV signaling to acquire EMP and progress to the aggressive mesenchymal state in response to TME-derived factors. In addition, ITGAV allows the identification of these epithelial plastic cancer cells and functions as a prognostic biomarker of tumor relapse.

The fibroblast heterogeneity across keloid, normal and tumor samples from single-cell resolution.

Keloids are defined as a benign dermal fibroproliferative disorder, with excessive fibroblast proliferation, and excessive overproduction of collagen. Although the heterogeneity during keloid development has been extensively studied, the heterogeneity across different skin states is still unclear. So, a global comparison across skin states is needed. In this study, we collected samples from 5 states of skin, including melanoma, cutaneous squamous cell carcinoma, keloid skin, scar skin, and healthy control samples. The heterogeneity of cell types and subtypes was analyzed and compared across 5 states, and we observed significant differences among them. Our results showed a cancer-like fibroblast, which is not in normal samples, may play an important role in antigen processing and presentation. We also noticed that the mesenchymal fibroblast increased in keloid samples, which highly expressed POSTN. And POSTN may participate in epithelial-mesenchymal transition and collagen overexpression to promote keloid growth. These findings help to understand the alteration among different skin states and provide potential genetic basis for keloid therapies.

Real-World Experience With Cemiplimab in Advanced Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common nonmelanoma skin cancer in Canada. However, few real-world reports exist on the treatment of refractory locally advanced (LA) and metastatic cSCC with cemiplimab to date. The objective of this study was to characterize the demographic and clinical outcomes of advanced cSCC patients on cemiplimab in a real-world setting. Retrospective analysis of adult patients with refractory LA and metastatic cSCC treated with cemiplimab at the London Regional Cancer Program in Canada. Patient demographics and treatment characteristics were reported, as well as Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS). Forty patients were included in this study. Sixteen (40%) had LA disease and 24 (60%) had metastatic disease. Median treatment duration was 3.5 months (range: 0.6-29.4 months). Kaplan-Meier analyses of the entire study population revealed that the median OS was not reached [NR; 95% confidence interval (CI) 9.1 months-NR], but median PFS was 11.5 months (95% CI 7.0 months-NR). A total of 25% of patients experienced at least one adverse event from cemiplimab. Reasons for treatment discontinuation were death from any cause (25%), disease progression (15%), cemiplimab adverse events (5%), and other causes (15%). The 12 month estimates of OS and PFS were lower than pivotal phase I and II clinical trials. However, toxicity was tolerable. Cemiplimab remains a safe and effective therapy in patients with refractory LA and metastatic cSCC disease.

Case report: Evaluation of cutaneous squamous cell carcinoma metastasized to lymph nodes using 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in a dog

Case report: Evaluation of cutaneous squamous cell carcinoma metastasized to lymph nodes using 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in a dog

Reconceiving perineural invasion in cutaneous squamous cell carcinoma: from biological to histopathological assessment.

Background Perineural invasion (PNI) is a complex molecular process histologically represented by the presence of tumor cells within the peripheral nerve sheath and defined when infiltration into the 3 nerve sheath layers can be clearly identified. Several molecular pathways have been implicated in cSCC. PNI is a well-recognized risk factor in cutaneous squamous cell carcinoma (cSCC) and its accurate assessment represents a challenging field in pathology daily practice. Summary As a highly intricate and dynamic process, PNI involves a contingent on bidirectional signaling interactions between the tumor and various nerve components, such as Schwann cells and neurons. The current staging systems recommend the identification of PNI as a dichotomous variable (presence vs. absence) to identify a subgroup of high-risk patients. However, recent further insights revealed that the evaluation of morphological PNI-related features in cSCC may enhance the prognostic stratification of patients and may optimize the current staging guidelines for recurrence risk assessment and improvement of patient selection for post-operative adjuvant treatments. Furthermore, recent emerging biomarkers could redefine early PNI detection. Key Messages This review provides updated insights into cSCC with PNI, focusing on molecular and cellular pathogenic processes, and aims to increase knowledge on prognostic relevant PNI-related histological features.

Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma.

We performed multi-omic profiling of epidermal keratinocytes, precancerous actinic keratoses, and squamous cell carcinomas to understand the molecular transitions during skin carcinogenesis. Single-cell mutational analyses showed that most keratinocytes in normal skin had lower mutation burdens than melanocytes and fibroblasts, however keratinocytes with TP53 or NOTCH1 mutations had substantially higher mutation burdens, suggesting that these mutations prime keratinocytes for transformation by increasing their mutation rate. Mutational profiling and spatial transcriptomics on squamous cell carcinomas adjacent to actinic keratoses revealed TERT promoter and CDKN2A mutations emerging in actinic keratoses, whereas additional mutations inactivating ARID2 and activating the MAPK-pathway delineated the transition to squamous cell carcinomas. Spatial variation in gene expression patterns was common in both tumor and immune cells, with high expression of checkpoint molecules at the invasive front of tumors. In conclusion, this study documents key events during the evolution of cutaneous squamous cell carcinoma.

Advancing Research in Cutaneous Squamous Cell Carcinoma—Precision Management Requires Precision Data

Advancing Research in Cutaneous Squamous Cell Carcinoma—Precision Management Requires Precision Data

Clustering of RNA co-expression network identifies novel long non-coding RNA biomarkers in squamous cell carcinoma

Long non-coding RNAs (lncRNAs) have emerged as important players in cancer progression. Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer with increasing incidence worldwide. The prognosis of the metastatic cSCC is poor, and currently there are no established biomarkers to predict metastasis risk or specific therapeutic targets for advanced or metastatic cSCC. To elucidate the role of lncRNAs in cSCC, RNA sequencing of patient derived cSCC cell lines and normal human epidermal keratinocytes was performed. The correlation analysis of differentially expressed lncRNAs and protein-coding genes revealed six distinct gene clusters with one of the upregulated clusters featuring genes associated with cell motility. Upregulation of the expression of lncRNAs linked to cSCC cell motility in cSCC and head and neck SCC (HNSCC) cells was confirmed using qRT-PCR. Elevated expression of HOTTIP and LINC00543 was also noted in SCC tumors in vivo and was associated with poorer prognosis in HNSCC and lung SCC cohorts within TCGA data, respectively. Altogether, these findings uncover a novel set of lncRNAs implicated in cSCC cell locomotion. These lncRNAs may serve as potential novel biomarkers and as putative therapeutic targets for locally advanced and metastatic cSCC.

Re-Treatment With Immune Checkpoint Inhibitors

We did not find any evidence regarding the clinical effectiveness and safety of second re-treatment with pembrolizumab for non–small cell lung cancer, classical Hodgkin lymphoma, and advanced melanoma. We did not find any evidence regarding the clinical effectiveness and safety of second re-treatment with cemiplimab for cutaneous squamous cell carcinoma. We did not find any evidence-based guidelines regarding the second re-treatment with immune checkpoint inhibitors for non–small cell lung cancer, classical Hodgkin lymphoma, advanced melanoma, and cutaneous squamous cell carcinoma.

Emerging Indications for Neoadjuvant Systemic Therapies in Cutaneous Malignancies

Patients with cutaneous malignancies and locoregional involvement represent a high-risk population for disease recurrence, even if they receive optimal surgery and adjuvant treatment. Here, we discuss how neoadjuvant therapy has the potential to offer significant advantages over adjuvant treatment, further improving outcomes in some patients with skin cancers, including melanoma, Merkel cell carcinoma, and cutaneous squamous-cell carcinoma. Both preclinical studies and in vivo trials have demonstrated that exposure to immunotherapy prior to surgical resection can trigger a broader and more robust immune response, resulting in increased tumor cell antigen presentation and improved targeting by immune cells, potentially resulting in superior outcomes. In addition, neoadjuvant approaches hold the possibility of providing a platform for evaluating pathological responses in the resected lesion, optimizing the prognosis and enabling personalized adaptive management, in addition to expedited drug development. However, more data are still needed to determine the ideal patient selection and the best treatment framework and to identify reliable biomarkers of treatment responses. Although there are ongoing questions regarding neoadjuvant treatment, current data support a paradigm shift toward considering neoadjuvant therapy as the standard approach for selecting patients with high-risk skin tumors.

Histological deep margins in cutaneous squamous cell carcinoma of the scalp and risk of recurrence.

Consensus is lacking on adequate deep histological margins in cutaneous squamous cell carcinoma (cSCC). Deep clearance for tumours located on the scalp is limited by anatomic constraints. To determine whether clear but close deep histological margins (<1 mm) confer a higher risk of recurrence in cSCCs of the scalp treated by wide local excision, compared to deep histological margins ≥1 mm. Multicentre retrospective observational cohort study and multivariate competing risk analysis to evaluate risk factors for recurrence. In total, 295 patients with 338 cSCCs were included. Close deep histological margins were not associated with an increased cumulative incidence of recurrence (subhazard ratio [SHR] 1.96 [95% CI 0.87-4.41]). However, an increased risk of recurrence was observed for those tumours that presented concurrent invasion of the galea aponeurotica and close deep margins, as opposed to patients without these factors (SHR 3.52 [1.24-10.01]). Tumours with clear but close peripheral margins (<1 mm) also had higher risk of recurrence (SHR 5.01 [1.68-14.97]). Retrospective observational study based on pathology reports. Deep histological margins <1 mm do not confer a greater risk of recurrence as long as the tumour is completely excised and the galea aponeurotica is not involved. Surgical excision of cSCC on the scalp should include the galea to ensure proper assessment of deep margins.

RBM3 Inhibits the Cell Cycle of Cutaneous Squamous Cell Carcinoma through the PI3K/AKT Signaling Pathway.

RBM3 is a key RNA-binding protein that has been implicated in various cellular processes, including cell proliferation and cell cycle regulation. However, its role in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. We aimed to investigate the expression levels of RNA-binding motif protein 3 (RBM3) in patients with cSCC and evaluate its effect on cell ability in cSCC and its underlying regulatory mechanisms. The expression of RBM3 in cSCC tissues and A431 cells was determined via immunohistochemistry and western blotting. Plenti-CMV-RBM3- Puro was used to overexpress RBM3. The effect of RBM3 on the proliferation ability of cSCC cells was evaluated using MTT and colony formation assay. Cell apoptosis and cell cycle were determined using flow cytometry, while the protein expressions of BAX, NF-κB, BCL2, CASPASE 3, CYCLIN B, CYCLIN E, CDK1, phosphorylated (P)-CDK1, CDK2, P-CDK2, ERK, P-ERK, P-AMPK, AKT, P-AKT, MDM2, and P53 were assessed using western blotting. RBM3 expression was significantly downregulated in cSCC tissues and A431 cells. RBM3 overexpression significantly inhibited the cell proliferation and colony formation ability of A431. Notably, RNA-seq results showed that the differentially expressed genes associated with RBM3 were primarily involved in the regulation of the cell cycle, oocyte meiosis, and P53 signaling pathway, as well as the modulation of the MAPK, AMPK, Hippo, mTOR, PI3K/AKT, Wnt, FoxO, and NF-κB signaling pathways. Additionally, our findings demonstrated that overexpression of RBM3 inhibited cell proliferation and induced cell cycle arrest of cSCC through modulation of the PI3K/AKT signaling pathway. This study provides novel insights into the suppressive roles of RBM3 in cell proliferation and the cell cycle in cSCC and highlights its therapeutic potential for cSCC.

Biomarkers in Cutaneous Keratinocyte Carcinomas.

Skin cancer is the most common cancer type in the USA, with over fivemillion annually treated cases and one in five Americans predicted to develop the disease by the age of 70. Skin cancer can be classified as melanoma or non-melanoma (NMSC), the latter including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC). Development of BCC and SCC is impacted by environmental, behavioral, and genetic risk factors and the incidence is on the rise, with the associated number of deaths surpassing those caused by melanoma, according to recent reports. Substantial morbidity is related to both BCC and SCC, including disfigurement, loss of function, and chronic pain, driving high treatment costs, and representing a heavy financial burden to patients and healthcare systems worldwide. Clinical presentations of BCC and SCC can be diverse, sometimes carrying considerable phenotypic similarities to benign lesions, and underscoring the need for the development of disease-specific biomarkers. Skin biomarker profiling plays an important role in deeper disease understanding, as well as in guiding clinical diagnosis and patient management, prompting the use of both invasive and non-invasive tools to evaluate specific biomarkers. In this work, we review the known and emerging biomarkers of BCC and SCC, with a focus on molecular and histologic biomarkers relevant for aspects of patient management, including prevention/risk assessments, tumor diagnosis, and therapy selection.