Microscopic view of S100A8 protein differentiating squamous cell carcinoma cells.

S100A8: The Unexpected Key to Squamous Cell Carcinoma Differentiation

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Jordan Keane in Health & Wellness August 2025 • 4 min read.

"Discover how S100A8 protein plays a vital role in cutaneous squamous cell carcinoma, opening new avenues for targeted treatments and improved outcomes."


Cutaneous squamous cell carcinoma (SCC) is a prevalent type of non-melanoma skin cancer, arising from the epidermal keratinocytes. As one of the most common cutaneous cancers among older adults, understanding its development and potential treatments is crucial. Most SCC cases evolve from precursor lesions such as actinic keratosis (AK) and Bowen’s disease. Actinic keratosis, in particular, is often the initial lesion that progresses into invasive cutaneous SCC.

S100 proteins are a family of cytoplasmic Ca2+-binding proteins, exhibiting differential expression across various cell types. These proteins are found in neutrophils, monocytes, and macrophages, and are released upon phagocyte activation. S100A8, also known as calgranulin A or migration inhibitory factor-related protein 8, is a member of the S100 protein family and often forms heteromeric calprotectin with S100A9. While S100A8 and S100A9 typically form heteromeric protein complexes, individual S100 proteins can also have distinct functions.

Recent research has highlighted the association of S100A8 with various malignant disorders. Genomic abnormalities in the chromosomal region 1q21, where many S100 genes are clustered, are frequently observed in epithelial cancers, including lung, breast, colorectal, and liver cancer. Differential S100A8 expression has also been noted in numerous neoplastic diseases. In tumors of glandular cell origin, S100A8/A9 expression correlates with poor cell differentiation. However, there remains limited research on S100A8 expression in cutaneous SCC and its relationship with cancer cell differentiation.

The Role of S100A8 in SCC Differentiation

Microscopic view of S100A8 protein differentiating squamous cell carcinoma cells.

A recent study investigated the differential expression of S100A8 in premalignant AK and cutaneous SCC, aiming to evaluate its role in cultured SCC cells through an adenoviral gene delivery system. The study demonstrated that S100A8 regulates cutaneous SCC differentiation and promotes well-differentiated SCC formation by modulating differentiation-related proteins. This groundbreaking research offers new insights into potential therapeutic strategies for managing SCC.

To explore the relationship between S100A8 and cutaneous SCC development, immunohistochemical staining was performed to detect S100A8 expression in facial skin specimens of pre-malignant actinic keratosis (AK), malignant SCC, and normal tissues. Additionally, post-confluence and high calcium-induced differentiation were utilized in a culture system model. A recombinant adenovirus expressing GFP-tagged S100A8 was constructed to further investigate S100A8's role in SCC cell differentiation.

  • S100A8 overexpression in SCC cells increased the expression of differentiation markers like loricrin, involucrin, and filaggrin.
  • S100A8 also significantly increased loricrin and involucrin luciferase activity.
  • These findings indicate that S100A8 regulates cutaneous SCC differentiation and promotes the formation of well-differentiated SCC in the skin.
The findings revealed that S100A8 was significantly overexpressed in human cutaneous SCC compared to normal and AK tissues. In a post-confluence-induced differentiation model, S100A8 was gradually upregulated in SCC cells. Overexpression of S100A8 in SCC cells, induced by adenoviral transduction, led to increased expression levels of differentiation markers such as loricrin, involucrin, and filaggrin. Furthermore, S100A8 overexpression increased loricrin and involucrin luciferase activity, underscoring its role in promoting differentiation.

The Future of SCC Treatment

In conclusion, this research confirms the significant overexpression of S100A8 in cutaneous SCC and indicates its role in inducing cancer cell differentiation, leading to the formation of well-differentiated SCC in the skin. S100A8 may play a key role in the development of less aggressive, lower-risk cutaneous SCC, characterized by reduced rates of recurrence and metastasis compared to SCCs from internal organs. Further investigations are essential to fully elucidate the molecular mechanisms of S100A8 in cutaneous SCC pathogenesis, potentially paving the way for new therapeutic interventions.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.5021/ad.2016.28.2.179, Alternate LINK

Title: Potential Role Of S100A8 In Cutaneous Squamous Cell Carcinoma Differentiation

Subject: Dermatology

Journal: Annals of Dermatology

Publisher: Korean Dermatological Association and The Korean Society for Investigative Dermatology

Authors: Jung-Min Shin, In-Kyu Chang, Young-Ho Lee, Min-Kyung Yeo, Jin-Man Kim, Kyung-Cheol Sohn, Myung Im, Young-Joon Seo, Chang-Deok Kim, Jeung-Hoon Lee, Young Lee

Published: 2016-01-01

Everything You Need To Know

1

What is cutaneous squamous cell carcinoma (SCC), and why is it important to study?

Cutaneous squamous cell carcinoma (SCC) is a type of skin cancer that originates from epidermal keratinocytes. It often begins as precursor lesions, such as actinic keratosis (AK) and Bowen’s disease. Understanding the progression and treatment of cutaneous SCC is critical, especially given its prevalence among older adults.

2

What is S100A8, and how does it relate to the S100 protein family?

S100A8 is a protein belonging to the S100 family of cytoplasmic Ca2+-binding proteins. It is found in cells like neutrophils, monocytes, and macrophages and is released during phagocyte activation. S100A8 often forms a heteromeric complex called calprotectin with S100A9, although S100A8 itself can have distinct functions.

3

How does the expression of S100A8 differ in cutaneous SCC compared to normal skin, and what effects does it have on SCC cells?

Research indicates that S100A8 is significantly overexpressed in cutaneous SCC compared to normal skin and actinic keratosis (AK) tissues. Overexpression of S100A8 in SCC cells leads to increased levels of differentiation markers like loricrin, involucrin, and filaggrin, enhancing the differentiation process. S100A8 also increases loricrin and involucrin luciferase activity, further promoting differentiation.

4

How does S100A8 affect the aggressiveness of cutaneous SCC, and what are the implications for cancer prognosis?

S100A8 promotes the formation of well-differentiated cutaneous SCC. Well-differentiated SCC tends to be less aggressive and carries lower risks of recurrence and metastasis compared to SCCs originating from internal organs. By inducing cancer cell differentiation, S100A8 could play a role in mitigating the severity of cutaneous SCC.

5

What are the next steps in researching S100A8's role in cutaneous SCC, and how could this research contribute to new treatments?

Further research is needed to fully understand the molecular mechanisms of S100A8 in cutaneous SCC pathogenesis. Understanding these mechanisms could lead to the development of new therapeutic interventions targeting S100A8. Future studies may explore how S100A8 interacts with other molecules and pathways involved in cutaneous SCC development, which could identify potential drug targets or therapeutic strategies.

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