Metastatic cutaneous squamous cell carcinoma treated successfully with surgery,radiotherapy and S‐1/cisplatin chemotherapy

Primary cutaneous squamous cell carcinoma (SCC) is a malignant tumor that arises from keratinizing cells of the epidermis or its appendages. We present a patient with cutaneous SCC on the left instep with metastases to multiple lymph nodes in the para‐aortic, iliac and groin region. We chose a combination of surgery and concurrent chemoradiotherapy. The chemotherapeutic agent S‐1/cisplatin was selected based on results of the histoculture drug response assay. The patient responded dramatically to this multidisciplinary treatment and complete remission was achieved.     

Oral S‐1 in advanced cutaneous squamous cell carcinoma

Squamous cell carcinoma (SCC) is the second most common type of skin cancer in Japan, and its incidence has been increasing in recent years. Early diagnosis and complete excision can provide a high cure rate. However, advanced cases of SCC showing local invasion, regional lymph node metastasis or distant metastasis are not curative and are difficult to treat with surgery alone. Some chemotherapy regimens have been used for treating advanced cutaneous SCC. However, almost all these regimens require intravenous administration and result in serious toxicities in elderly people. We gave S‐1, a novel oral chemotherapeutic agent, for six patients with advanced cutaneous SCC. Three patients achieved complete response and one achieved partial response. Two patients showed stable disease. The overall response rate was 66.7% (four of six patients), and the disease control rate was 100%. Two of six patients developed grade 3 anaemia. Oral S‐1 treatment is safe and effective for treating advanced cutaneous SCC. However, a prospective trial is necessary to confirm the effectiveness of oral S‐1 for advanced cutaneous SCC.     

Axin1、Gsk-3β和CD82在皮肤鳞状细胞癌中的表达

目的：检测Axin1、Gsk-3β和CD82蛋白在皮肤鳞癌中的表达。方法：40例皮肤鳞状细胞癌（cSCC）作为实验组，15例正常皮肤组织作为对照组，采用免疫组织化学方法检测Axin1、Gsk-3β和CD82在两组中的表达。结果：Axin1在正常皮肤、cSCC I级、II级、III级的阳性表达率分别为86.7%、66.7%、40.0%、10.0%，Gsk-3β分别为80.0%、73.3%、20.0%、20.0%，CD82阳性表达率分别为73.3%、60.0%、26.7%、10.0%。在cSCC中Axin1与Gsk-3β表达呈正相关（r=0.677，P＜0.05）。结论：Axin1、Gsk-3β和CD82可能与cSCC肿瘤发展有关。     

Update on the anti‐programmed cell death‐1 receptor antibodies in advanced cutaneous squamous‐cell carcinoma

Regarding the rising incidence and the not negligible mortality, the treatment of cutaneous squamous‐cell carcinoma (cSCC) has a high clinical relevance. Immune checkpoint inhibitors (ICI), especially anti‐programmed cell death‐1 receptor (anti‐PD‐1) antibodies such as pembrolizumab and cemiplimab have shown promising results in Phase 2 studies for patients with locally advanced and/or metastatic cSCC. We are presenting a review of the latest results in the treatment of cSCC with ICI. Patients with locally advanced or metastatic cSCC have been treated with cemiplimab 3 mg/kg every 2 weeks. For locally advanced cSCC, an objective response was observed in 44% of patients, 13% patients with a complete response, and 31% with a partial response. For metastatic patients, the overall response rate was 49.2%. The approved dose for cemiplimab in the United States and Europe is 350 mg every 3 weeks. These ICI seem to achieve higher response rates compared with epidermal growth factor receptor (EGFR) inhibitors, with a durable response superior to both chemotherapy and EGFR inhibitors. The side effect profile of anti‐PD‐1 antibodies appears to be favorable compared to chemotherapy. In this way, PD‐1 inhibitors are expected to become the new gold‐standard treatment for patients with locally advanced and metastatic cSCC.     

Epigenetic abnormalities in cutaneous squamous cell carcinomas: frequent inactivation of the RB1/p16 and p53 pathways

BACKGROUND: Aberrant methylation of CpG islands in the promoter regions of cancer-related genes has been demonstrated in many human tumours. However, the methylation profile of these regions in cutaneous squamous cell carcinomas (SCCs) has not been well studied. OBJECTIVES: To examine epigenetic abnormalities of a wide range of cancer-related genes in SCCs. METHODS: We investigated the methylation status of 11 candidate cancer-related genes (CDH1, p16(INK4a), p14(ARF), DAPK1, MGMT, RB1, RASSF1, p15(INK4b), PTEN, PRDM2 and p53) in 20 cases of SCC by methylation-specific polymerase chain reaction, and comparatively examined the protein production of E-cadherin (CDH1), p16, RB1, p14, BMI1 and cyclin A by immunohistochemical analysis. RESULTS: The frequency of cancer-related gene methylation in SCCs was: CDH1 (95%), p16 (20%), p14 (15%), DAPK1 (15%), MGMT (15%), RB1 (5%), RASSF1 (5%), p15 (0%), PTEN (0%), PRDM2 (0%) and p53 (0%). Almost all cases with hypermethylation of CDH1, p16, RB1 and p14 showed no obvious production of each protein, suggesting that promoter hypermethylation of these genes contributes to the loss of protein production. The results of methylation analysis, in combination with the results of our previous mutation analysis of CDKN2A locus and p53, revealed that 70% of SCCs have alterations in the RB1/p16 or p53 pathway. CONCLUSIONS: Our findings indicate that the promoter hypermethylation of cancer-related genes, especially CDH1, is frequently shown in SCCs, and dysregulation of the RB1/p16 and/or p53 pathway through either genetic or epigenetic mechanisms, except for epigenetic abnormalities of p53 itself, should contribute to the carcinogenesis of SCCs.     

A comparative study of the effectiveness of cisplatin and 5‐fluorouracil on cutaneous squamous human carcinoma cell line: Potential chemotherapy alternative to surgery

Surgery as treatment for local invasive cutaneous squamous cell carcinoma (cSCC) is not always feasible due to the age and/or the health status of patients. Thus, the investigation of new strategies to improve the quality of life of them is required. The aim of this work is to investigate two chemotherapy agents individually on cSCC cells with the purpose to provide a better understanding of the effectiveness underlying each one. The cisplatin effectiveness is compared at different times with that observed for the 5‐fluorouracil treatment. The effectiveness of both was assessed by using flow cytometry to determine the survival cell ratio, and QBlue test to study the cell recovery ability after treatments. A significant increase in the number of apoptotic cells, especially 48 hours after treatments, has been detected. Despite this, cisplatin arises as the most promising agent for the treatment of local invasive cutaneous squamous cell carcinoma due to the fact that a lower concentration and time are required to observe a higher effectiveness on cells with respect to the 5‐fluorouracil. An optimal cisplatin‐based chemotherapy might provide a better outcome for patients affected by a local invasive cSCC rather than surgery.     

Prognostic significance of expression of p53 protein and Ki-67 antigen in well-differentiated squamous cell carcinoma of the skin

Prognostic Significance of Expression of p53 Protein and Ki-67 Antigen in Well-Differentiated Squamous Cell Carcinoma of the Skin     

脂溢性角化病、基底细胞癌和鳞状细胞癌中几种Smad蛋白质表达的检测

目的：探讨转化生长因子（TGF）-β信号转导途径中Smad1、Smad2、Smad3（Smad1／2／3）,磷酸化Smad2,磷酸化Smad3（p-Smad2／3）Smad4蛋白在脂溢性角化病、基底细胞癌和鳞状细胞癌中的表达特点及其意义。方法：采用EliVision^TMplus免疫组化技术分别检测脂溢性角化病、基底细胞癌、鳞状细胞癌以及正常对照皮肤中Smad1／2／3、p-Smad2／3、和Smad4的表达情况。结果：Smad1／2／3、p-Smad2／3和Smad4蛋白在脂溢性角化病、基底细胞癌和鳞状细胞癌中的表达较正常表皮显著降低。结论：脂溢性角化病、鳞状细胞癌和基底细胞癌中Smadl／2／3、p-Smad2／3和Smad4蛋白表达降低可能通过阻断TGF—B信号转导,有助于上述表皮肿瘤的形成和发展。     

miR-196-5 p靶向HOXA5激活JAK/STAT通路促进皮肤鳞状细胞癌的增殖、侵袭及EMT

目的:探讨miR-196-5p对皮肤鳞状细胞癌(CSCC)增殖、侵袭和EMT的影响及其潜在的作用机制.方法:利用实时荧光定量PCR(RT-qPCR)检测miR-196-5 p在癌旁正常组织、CSCC组织、A431细胞和HaCaT细胞中的表达水平.过表达或下调miR-196-5 p在A431细胞中的表达后,通过CCK-8...     

Aldo‐keto reductase 1C3 is overexpressed in skin squamous cell carcinoma (SCC) and affects SCC growth via prostaglandin metabolism

Aldo‐keto reductase 1C3 (AKR1C3) is an enzyme involved in metabolizing prostaglandins (PGs) and sex hormones. It metabolizes PGD₂ to 9α11β‐PGF₂, diverting the spontaneous conversion of PGD₂ to the PPARγ agonist, 15‐Deoxy‐Delta‐12, 14‐prostaglandin J2 (15d‐PGJ₂). AKR1C3 is overexpressed in various malignancies, suggesting a tumor promoting function. This work investigates AKR1C3 expression in human non‐melanoma skin cancers, revealing overexpression in squamous cell carcinoma (SCC). Effects of AKR1C3 overexpression were then evaluated using three SCC cell lines. AKR1C3 was detected in all SCC cell lines and its expression was upregulated in response to its substrate, PGD₂. Although attenuating AKR1C3 expression in SCC cells by siRNA did not affect growth, treatment with PGD₂ and its dehydration metabolite, 15d‐PGJ₂, decreased SCC proliferation in a PPARγ‐dependent manner. In addition, treatment with the PPARγ agonist pioglitazone profoundly inhibited SCC proliferation. Finally, we generated an SCC cell line that stably overexpressed AKR1C3 (SCC‐AKR1C3). SCC‐AKR1C3 metabolized PGD₂ to 9α11β‐PGF₂ 12‐fold faster than the parent cell line and was protected from the antiproliferative effect mediated by PGD₂. This work suggests that PGD₂ and its metabolite 15d‐PGJ₂ attenuate SCC proliferation in a PPARγ‐dependent manner, therefore activation of PPARγ by agonists such as pioglitazone may benefit those at high risk of SCC.     

lncRNA DLX6-AS1通过靶向miR-16-5p/NUCKS1调控皮肤鳞状细胞癌细胞A431增殖、迁移和侵袭

【摘要】 目的 研究长链非编码生长停滞特异性蛋白6反义RNA1（lncRNA DLX6-AS1）对皮肤鳞状细胞癌细胞A431增殖、迁移和侵袭的影响及潜在机制。方法 以双荧光素酶报告系统实验验证lncRNA DLX6-AS1与miR-16-5p、miR-16-5p与核酪蛋白激酶和细胞周期蛋白依赖性激酶底物1（NUCKS1）mRNA的靶向结合。通过单独或联合转染lncRNA DLX6-AS1抑制物（si-DLX6-AS1）、miR-16-5p抑制物（anti-miR-16-5p）、NUCKS1抑制物（si-NUCKS1）和相应对照（DLX6-AS1-NC、anti-miR-NC、NUCKS1-NC）调控A431细胞目的基因的表达,采用qRT-PCR 检测A431细胞lncRNA DLX6-AS1、miR-16-5p、NUCKS1 mRNA的表达;Western印迹检测NUCKS1、细胞周期蛋白D1（Cyclin D1）抗体、基质金属蛋白酶（MMP）2和MMP9蛋白水平;CCK8实验检测细胞存活率;Transwell实验检测细胞迁移和侵袭能力。两组间比较采用独立样本t检验。结果 双荧光素酶报告系统实验显示,lncRNA DLX6-AS1靶向结合miR-16-5p,miR-16-5p靶向结合NUCKS1。si-DLX6-AS1组A431细胞miR-16-5p表达水平（3.01 ± 0.31）高于DLX6-AS1-NC组（1.02 ± 0.10,t = 18.33,P < 0.001）;NUCKS1、Cyclin D1、MMP2和MMP9蛋白相对水平均低于DLX6-AS1-NC组（均P < 0.05）,细胞存活率、迁移和侵袭细胞数亦低于DLX6-AS1-NC组（均P < 0.05）。si-NUCKS1组A431细胞NUCKS1、Cyclin D1、MMP2和MMP9蛋白相对水平均低于NUCKS1-NC组（均P < 0.05）,细胞存活率、迁移和侵袭细胞数亦低于NUCKS1-NC组（均P < 0.05）。低表达lncRNA DLX6-AS1后,anti-miR-16-5p组A431细胞miR-16-5p表达（0.34 ± 0.04）低于anti-miR-NC组（1.00 ± 0.12,t = 15.65,P < 0.05）,Cyclin D1、MMP2和MMP9相对表达水平均高于anti-miR-NC组（均P < 0.05）,细胞存活率、迁移和侵袭细胞数均高于anti-miR-NC组（均P < 0.05）。低表达lncRNA DLX6-AS1、敲减miR-16-5p后,si-NUCKS1组A431细胞NUCKS1、Cyclin D1、MMP2和MMP9蛋白相对水平均低于NUCKS1-NC组（P < 0.05）,细胞存活率、迁移和侵袭细胞数均低于NUCKS1-NC组（P < 0.05）。结论 lncRNA DLX6-AS1可通过靶向miR-16-5p/NUCKS1调控A431细胞增殖、迁移和侵袭,lncRNA DLX6-AS1可能是治疗皮肤鳞状细胞癌的潜在分子靶点。     

Activation of the PI3K/AKT signalling pathway in non‐melanoma skin cancer is not mediated by oncogenic PIK3CA and AKT1 hotspot mutations

Please cite this paper as: Activation of the PI3K/AKT signalling pathway in non‐melanoma skin cancer is not mediated by oncogenic PIK3CA and AKT1 hotspot mutations. Experimental Dermatology 2010; 19 : e222–e227. Abstract: Non‐melanoma skin cancer represents the most frequent human cancer entity. Activation of the PI3K/AKT signalling pathway has been reported both in squamous cell carcinoma (SCC) of the skin and in basal cell carcinoma (BCC). In many cancers, including SCC of the head and neck, the oesophagus and the penis, activation of this pathway is mediated by oncogenic PIK3CA and AKT1 mutations. We therefore screened 61 non‐melanoma skin cancer samples (30 SCC and 31 BCC) for the presence of activating PIK3CA and AKT1 mutations. PIK3CA hotspot mutations were analysed using a highly sensitive SNaPshot assay, and exon 4 of AKT1 was sequenced directly. In addition, immunohistochemistry was performed for phosphorylated AKT protein. Immunohistochemical expression of pAkt was observed both in SCC and in BCC samples, indicating an activation of the PI3K/AKT pathway. Although SCC showed higher expression levels than BCC, this difference was not significant. However, none of the 61 non‐melanoma skin cancer samples revealed any PIK3CA and AKT1 hotspot mutations at the investigated loci. We conclude that PIK3CA and AKT1 hotspot mutations do not contribute to the activation of the PI3K/AKT signalling pathway in non‐melanoma skin cancer. The distinct PIK3CA mutation spectrum between SCC of the skin and SCC of other tissues may reflect the different carcinogens which are involved into the mutagenesis of these cancers. PIK3CA and AKT1 hotspot mutations are obviously not caused by UV light exposure, the main risk factor in non‐melanoma skin cancer.