The Role of p53 in Progression of Cutaneous Squamous Cell Carcinoma

Piipponen, Minna; Riihilä, Pilvi; Nissinen, Liisa; Kähäri, Veli‐Matti

doi:10.3390/cancers13184507

Cited by 44 publications

(39 citation statements)

References 179 publications

(419 reference statements)

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“…The mutation of the TP53 gene and inactivation of the tumor suppressor p53 in epidermal keratinocytes is an early event in epidermal carcinogenesis, which results in the accumulation of oncogenic mutations required for the progression of AK to invasive cSCC [ 49 ]. In order to assess the role of FD as a potential molecular marker for cutaneous carcinogenesis, an in vitro model of different stages of keratinocyte carcinogenesis was developed and tested [ 34 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Complement Factor D Is a Novel Biomarker and Putative Therapeutic Target in Cutaneous Squamous Cell Carcinoma

Nezhad

Riihilä

Knuutila

et al. 2022

Cancers

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Cutaneous squamous cell carcinoma (cSCC) is the most prevalent metastatic skin cancer. Previous studies have demonstrated the autocrine role of complement components in cSCC progression. We have investigated factor D (FD), the key enzyme of the alternative complement pathway, in the development of cSCC. RT-qPCR analysis of cSCC cell lines and normal human epidermal keratinocytes (NHEKs) demonstrated significant up-regulation of FD mRNA in cSCC cells compared to NHEKs. Western blot analysis also showed more abundant FD production by cSCC cell lines. Significantly higher FD mRNA levels were noted in cSCC tumors than in normal skin. Strong tumor cell-associated FD immunolabeling was detected in the invasive margin of human cSCC xenografts. More intense tumor cell-specific immunostaining for FD was seen in the tumor edge in primary and metastatic cSCCs, in metastases, and in recessive dystrophic epidermolysis bullosa-associated cSCCs, compared with cSCC in situ, actinic keratosis and normal skin. FD production by cSCC cells was dependent on p38 mitogen-activated protein kinase activity, and it was induced by interferon-γ and interleukin-1β. Blocking FD activity by Danicopan inhibited activation of extracellular signal-regulated kinase 1/2 and attenuated proliferation of cSCC cells. These results identify FD as a novel putative biomarker and therapeutic target for cSCC progression.

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Section: Discussionmentioning

confidence: 99%

Complement Factor D Is a Novel Biomarker and Putative Therapeutic Target in Cutaneous Squamous Cell Carcinoma

Nezhad

Riihilä

Knuutila

et al. 2022

Cancers

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“…In genetically unstable cells, p53 can induce apoptosis, maintaining tissue homeostasis and tumor suppression [ 357 ]. However, loss-of-function of tumor suppressor p53 mutation, which is very frequent in the skin due to the repeated UV insult, impairs the physiological DNA repair machinery activity leading to the accumulation of further oncogenic mutations and expansion of pre-neoplastic clones [ 358 ]. Consistent with the early involvement of p53 in skin carcinogenesis, a wide number of studies documented p53 mutation in AK [ 359 ].…”

Section: Contribution Of Ros In Common Age-related Skin Diseasesmentioning

confidence: 99%

Focus on the Contribution of Oxidative Stress in Skin Aging

et al. 2022

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Skin aging is one of the most evident signs of human aging. Modification of the skin during the life span is characterized by fine lines and wrinkling, loss of elasticity and volume, laxity, rough-textured appearance, and pallor. In contrast, photoaged skin is associated with uneven pigmentation (age spot) and is markedly wrinkled. At the cellular and molecular level, it consists of multiple interconnected processes based on biochemical reactions, genetic programs, and occurrence of external stimulation. The principal cellular perturbation in the skin driving senescence is the alteration of oxidative balance. In chronological aging, reactive oxygen species (ROS) are produced mainly through cellular oxidative metabolism during adenosine triphosphate (ATP) generation from glucose and mitochondrial dysfunction, whereas in extrinsic aging, loss of redox equilibrium is caused by environmental factors, such as ultraviolet radiation, pollution, cigarette smoking, and inadequate nutrition. During the aging process, oxidative stress is attributed to both augmented ROS production and reduced levels of enzymatic and non-enzymatic protectors. Apart from the evident appearance of structural change, throughout aging, the skin gradually loses its natural functional characteristics and regenerative potential. With aging, the skin immune system also undergoes functional senescence manifested as a reduced ability to counteract infections and augmented frequency of autoimmune and neoplastic diseases. This review proposes an update on the role of oxidative stress in the appearance of the clinical manifestation of skin aging, as well as of the molecular mechanisms that underline this natural phenomenon sometimes accelerated by external factors.

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“…Important risk factors of cSCC are solar UV radiation, chronic ulcers, and immunosuppression [ 8 ]. During keratinocyte carcinogenesis tumor protein 53 ( TP53 ) gene is mutated early in cSCC development, resulting in a marked accumulation of additional UV-induced mutations [ 9 , 10 , 11 ]. Other genes commonly mutated in cSCC are NOTCH1 , HRAS , and CDKN2A [ 10 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Super Enhancer-Regulated LINC00094 (SERLOC) Upregulates the Expression of MMP-1 and MMP-13 and Promotes Invasion of Cutaneous Squamous Cell Carcinoma

Piipponen

Riihilä

Knuutila

et al. 2022

Cancers

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Long non-coding RNAs (lncRNAs) have emerged as important regulators of cancer progression. Super enhancers (SE) play a role in tumorigenesis and regulate the expression of specific lncRNAs. We examined the role of BRD3OS, also named LINC00094, in cutaneous squamous cell carcinoma (cSCC). Elevated BRD3OS (LINC00094) expression was detected in cSCC cells, and expression was downregulated by SE inhibitors THZ1 and JQ1 and via the MEK1/ERK1/2 pathway. Increased expression of BRD3OS (LINC00094) was noted in tumor cells in cSCCs and their metastases compared to normal skin, actinic keratoses, and cSCCs in situ. Higher BRD3OS (LINC00094) expression was noted in metastatic cSCCs than in non-metastatic cSCCs. RNA-seq analysis after BRD3OS (LINC00094) knockdown revealed significantly regulated GO terms Cell-matrix adhesion, Basement membrane, Metalloendopeptidase activity, and KEGG pathway Extracellular matrix–receptor interaction. Among the top-regulated genes were MMP1, MMP10, and MMP13. Knockdown of BRD3OS (LINC00094) resulted in decreased production of MMP-1 and MMP-13 by cSCC cells, suppressed invasion of cSCC cells through collagen I, and growth of human cSCC xenografts in vivo. Based on these observations, BRD3OS (LINC00094) was named SERLOC (super enhancer and ERK1/2-Regulated Long Intergenic non-protein coding transcript Overexpressed in Carcinomas). These results reveal the role of SERLOC in cSCC invasion and identify it as a potential therapeutic target in advanced cSCC.

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The Role of p53 in Progression of Cutaneous Squamous Cell Carcinoma

Cited by 44 publications

References 179 publications

Complement Factor D Is a Novel Biomarker and Putative Therapeutic Target in Cutaneous Squamous Cell Carcinoma

Complement Factor D Is a Novel Biomarker and Putative Therapeutic Target in Cutaneous Squamous Cell Carcinoma

Focus on the Contribution of Oxidative Stress in Skin Aging

Super Enhancer-Regulated LINC00094 (SERLOC) Upregulates the Expression of MMP-1 and MMP-13 and Promotes Invasion of Cutaneous Squamous Cell Carcinoma

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