Identification of differentially expressed genes in cutaneous squamous cell carcinoma by microarray expression profiling

Background  

Carcinogenesis is a multi-step process indicated by several genes up- or down-regulated during tumor progression. This study examined and identified differentially expressed genes in cutaneous squamous cell carcinoma (SCC).     

Identification of potential immune-related circRNA-miRNA-mRNA regulatory network in cutaneous squamous cell carcinoma

Circulating RNAs (circRNAs) are involved in tumor development and progression by participating in immune regulation. Nevertheless, the circRNAs expression profiles and their roles on the immunomodulatory effects in cutaneous squamous cell carcinoma (cSCC) have rarely been studied. In our study, we identified the differentially expressed circRNAs (DEcircRNAs), miRNAs (DEmiRNAs), mRNAs (DEmRNAs) in cSCC and established the circRNA competing endogenous RNAs (ceRNAs) network. Subsequently, the hub differentially expressed immune-related genes were identified and validated by immunochemistry as well as the GO and KEGG pathway analysis were performed. 54 differentially expressed circRNAs were identified and hub differentially expressed immune-related genes were identified and they were mostly associated with immune response in the progression of cSCC. Our results indicated that the potential immune-related circRNA-miRNA-mRNA network may assist in understanding the molecular mechanisms underlying the carcinogenesis and progression in cSCC. Moreover, the immune-related genes may provide an insight into the pathogenesis, molecular biomarkers, and potential therapeutic targets for cSCC patients.     

微小RNA在皮肤鳞状细胞癌中的研究进展

皮肤鳞状细胞癌(cSCC)是角质形成细胞来源的恶性肿瘤之一。转录组是特定条件下细胞内全部转录产物的总和,包括编码mRNA和非编码RNA。研究发现,与正常细胞相比,鳞癌细胞在基因转录水平和模式上存在很大差异,具有不同转录表达谱。微小RNA(miRNA)可通过抑制转录产物的翻译,从而调控靶基因的表达,影响cSCC细胞的增殖、分化和凋亡等病理过程。越来越多的研究表明,miRNAs作为cSCC诊断、预测预后和治疗靶点的生物标志物,在临床上具有广阔的应用前景。本文通过回顾分析cSCC的miRNA表达谱,主要对其中经实验证实表达上调和下调的miRNAs在cSCC中的研究进展作一综述。     

Methylthioadenosine phosphorylase expression in cutaneous squamous cell carcinoma

The methylthioadenosine phosphorylase (MTAP) gene is a tumour suppressor gene, located on chromosome 9p21, 100 kb telomeric of the p15 and p16 genes, which are often deleted in tumor cells. The role of MTAP protein expression in the genesis of cutaneous squamous cell carcinoma (SCC) is currently not known. In a previous study we have shown the frequent occurrence of allelic imbalance / loss of heterozygosity (AI/LOH) in cutaneous SCCs using AI/LOH markers flanking the p15, p16, and MTAP genes and demonstrated reduction in p15 and p16 protein expression in comparison to normal human skin. The present study is a continuation to our previous studies, aimed at determining possible roles played by MTAP protein expression in the genesis of cutaneous SCC. The expression of MTAP protein was detected using an immunohistochemical approach in a 109 micro array of cutaneous SCC and 20 normal human skin tissue samples. The expression of MTAP was not significantly different in the cutaneous SCC cases as compared with normal human skin. This may indicate that MTAP protein expression does not contribute to the genesis of cutaneous SCC.     

皮肤鳞状细胞癌研究进展

鳞状细胞癌在皮肤非黑色素细胞性恶性肿瘤中发病率居第二位,近年来发病率呈增高趋势。鳞状细胞癌病因复杂且临床表现无特异性,有时易导致误诊。虽然鳞状细胞癌通常生长较慢,但一些特殊类型可较早发生侵袭、转移。近年来,人们对鳞状细胞癌的认识逐渐深入,在其诊断、治疗、预防等方面研究成果显著。本文就鳞状细胞癌流行病学、病因、临床表现及病理、临床分期、治疗及预后等方面进行综述。     

皮肤鳞状细胞癌的外科治疗

目的 探讨皮肤鳞状细胞癌的外科治疗方法及效果。方法 收集1981年12月至2011年12月鳞状细胞癌105例,其中手术治疗101例。切除病灶后,根据创面不同部位、大小、深度,选择任意皮瓣、肌皮瓣或皮片修复创面;创面位于面部及关节部位采用分区植皮方法。结果病灶切除后,移植皮片48例,任意皮瓣或肌皮瓣修复53例;随诊6个月以上85例,随诊5年以上52例,16例发生局部复发或远处转移,其中8例死亡,其余患者术区外形良好,局部无复发。结论 皮肤鳞状细胞癌早期发现行完整手术切除仍然是最佳的治疗手段,对手术缺损可以采用整形美容方法修复,实现患者的生存时间和生活质量的提高。     

Identification of genes associated with cisplatin resistance in human oral squamous cell carcinoma cell line

Background  

Cisplatin is widely used for chemotherapy of head and neck squamous cell carcinoma. However, details of the molecular mechanism responsible for cisplatin resistance are still unclear. The aim of this study was to identify the expression of genes related to cisplatin resistance in oral squamous cell carcinoma cells.     

Identification of the optimal therapeutic antibody for fluorescent imaging of cutaneous squamous cell carcinoma

Intraoperative, real-time fluorescence imaging may significantly improve tumor visualization and resection and postoperatively, in pathological assessment. To this end, we sought to determine the optimal FDA approved therapeutic monoclonal antibody for optical imaging of human cutaneous squamous cell carcinoma (cSCC). A near-infrared (NIR) fluorescent probe (IRDye800) was covalently linked to bevacizumab, panitumumab or tocilizumab and injected systemically into immunodeficient mice bearing either cutaneous tumor cell lines (SCC13) or cutaneous human tumor explants. Tumors were then imaged and resected under fluorescent guidance with the SPY, an FDA-approved intraoperative imaging system, and the Pearl Impulse small animal imaging system. All fluorescently labeled antibodies delineated normal tissue from tumor in SCC13 xenografts based on tumor-to-background (TBR) ratios. The conjugated antibodies produced TBRs of 1.2–2 using SPY and 1.6–3.6 using Pearl; in comparison, isotype control antibody IgG-IRDye produced TBRs of 1.0 (SPY) and 0.98 (Pearl). Comparison between antibodies revealed them to be roughly equivalent for imaging purposes with both the SPY and Pearl (p = 0.89 SPY, p = 0.99 Pearl; one way ANOVA). Human tumor explants were also imaged and tumor detection was highest with panitumumab-IRDye800 when using the SPY (TBR 3.0) and Pearl (TBR 4.0). These data suggest that FDA approved antibodies may be clinically used for intraoperative detection of cSCC.     

Molecular and immune targets in cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and often confers a good prognosis. Though surgery is the gold standard of treatment, unresectable or metastatic disease can necessitate systemic therapy. Of systemic agents, there is increasing interest in the use of immunotherapies and targeted therapy. Further study into the driver mutations in cSCC has identified opportunities for targeted therapy. In this review, we discuss both current and investigational immune and molecular targets of therapy for cSCC.     

Identification and validation of dysregulated metabolic pathways in metastatic renal cell carcinoma

Metastatic renal cell carcinoma (mRCC) is a devastating disease with a 5-year survival rate of approximately 9 % and low response to chemotherapy and radiotherapy. Targeted therapies have slightly improved patient survival, but are only effective in a small subset of patients, who eventually develop resistance. A better understanding of pathways contributing to tumor progression and metastasis will allow for the development of novel targeted therapies and accurate prognostic markers. We performed extensive bioinformatics coupled with experimental validation on proteins dysregulated in mRCC. Gene ontology analysis showed that many proteins are involved in oxidation reduction, metabolic processes, and signal transduction. Pathway analysis showed metabolic pathways are altered in mRCC including glycolysis and pyruvate metabolism, the citric acid cycle, and the pentose phosphate pathway. RT-qPCR analysis showed that genes involved in the citric acid cycle were downregulated in metastatic RCC while genes of the pentose phosphate pathway were overexpressed. Protein–protein interaction analysis showed that most of the 198 proteins altered in mRCC clustered together and many were involved in glycolysis and pyruvate metabolism. We identified 29 reported regions of chromosomal aberrations in metastatic disease that correlate with the direction of protein dysregulation in mRCC. Furthermore, 36 proteins dysregulated in mRCC are predicted to be targets of metastasis-related miRNAs. A more comprehensive understanding of the pathways dysregulated in metastasis can be useful for the development of new therapies and novel prognostic markers. Also, multileveled analyses provide a unique “snapshot” of the molecular “environment” in RCC with prognostic and therapeutic implications.     

Fatal cutaneous squamous cell carcinoma in a forty-three-year-old male

A 43-year-old patient with a history of squamous cell carcinoma (SCC) of the lip, multiple actinic keratoses, and multiple sequential SCC on sun-exposed area of his skin developed a subcutaneous nodule of SCC in an area where a cutaneous SCC had been excised 1 year previously. At the time of the subcutaneous nodule there was no evidence of metastases; 5 months later he had metastatic bone disease as well as apparent metastases to myocardium, pericardium, and pleura. The patient is notable for the young age at primary diagnosis of SCC, the fulminant lethal course of a tumor which is generally considered curable, and a family history to which SCC occurred over three generations.     

Id proteins are dynamically expressed in normal epidermis and dysregulated in squamous cell carcinoma

Helix-loop-helix genes regulate many developmental pathways, and growing evidence associates dysregulated expression with tumorigenesis. We observed Id-1, Id-2, and Id-3 mRNA expression in proliferating human keratinocytes in vitro with subsequent down-regulation with differentiation. Immunohistochemical analysis of human tissue sections identified cytoplasmic Id-1 expression and nuclear Id-2 and Id-3 expression in the proliferating layers of the epidermis. Furthermore, we observed a columnar pattern of Id-2 and Id-3 staining, which may relate to the epidermal proliferative unit. In squamous cell carcinoma of the head and neck, Id protein immunoreactivity was observed in the majority of malignant keratinocytes in the most poorly differentiated sections, with reduced staining in well-differentiated disease.     

Treatment of unresectable and metastatic cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (SCC) is an already common disorder with a rapidly increasing incidence. Treatment of early disease depends primarily on surgery or destructive techniques. In contrast to the frequency of early SCC, unresectable or metastatic SCC is relatively rare, but potentially life-threatening without clearly proven treatment options. Few rigorous studies of the treatment of advanced SCC have been undertaken. In the past, various agents have been explored in a limited fashion, including chemotherapy (cisplatin, fluoropyrimidines, bleomycin, doxorubicin), 13-cis-retinoic acid, and interferon-α2a. Clinical activity has been suggested by these trials, but their small sizes, heterogeneous patient populations, and lack of randomization have hindered the use of their results in defining treatment paradigms. Only one rigorous randomized trial has focused on cutaneous SCC. Enrolling 66 patients, that trial randomized patients at high recurrence risk to either observation or postoperative interferon-α2a and 13-cis-retinoic acid. This treatment did not improve time to recurrence or prevent secondary cutaneous SCC from developing. Though not in the metastatic setting, this study casts doubt on the ability of this regimen to control metastatic disease. Recently, agents targeting the human epidermal growth factor receptor (erlotinib, gefitinib, cetuximab) have displayed preliminary evidence of activity in phase II clinical trials and case series reports. Expression of this receptor is frequent in cutaneous SCC and appears to be prognostically adverse. Only the conduct of rigorous trials, with well-defined endpoints, adequate patient numbers, and preferably randomization, can prove the clinical efficacy of this promising treatment approach and define better therapy for this vexing clinical problem.     

Identification and characterization of genes involved in the carcinogenesis of human squamous cell cervical carcinoma

We utilized RT-PCR differential display and cDNA microarrays to identify cellular genes involved in the multi-step carcinogenesis of squamous cell cervical carcinoma. Thirty-eight cervical cancer patients in various stages of the disease and 5 non-cervical cancer patients were studied. Twenty-five cDNA clones were identified and these were subsequently demonstrated to be consistently over-expressed in squamous cell cervical carcinoma biopsies of various FIGO stages. To further evaluate the possible role that these genes may play in the progression of disease, we performed Northern blot analysis and RNA-RNA in situ hybridization studies using cervical cancer biopsies of various FIGO stages. Of particular interest are the 2 clones G32C4B and G30CC that have been identified to be the NADH dehydrogenase 4 gene and the gene that encodes ribosomal protein S12 respectively when compared to sequences available in the GenBank database. Increased expression of these 2 genes were detected in the matched normal tissues collected together with the late FIGO stages of cervical cancer biopsies. In comparison, upregulation of these 2 genes was not detected in cervical squamous epithelium collected from patients admitted for surgery for non-malignant conditions, suggesting that expression of these 2 genes may have altered in the adjacent histopathologically "normal" cervical squamous epithelial tissue from cervical cancer patients. The ribosomal protein S12 and the NADH dehydrogenase 4 genes may therefore be potentially useful as early pre-transformation diagnostic markers for human cervical cancer.