Unveiling the Dual Role of a Protein in Healing and Cancer: Surprising Insights from Research

Long considered a simple indicator of aggressive cancers, the SerpinB3 protein is now establishing itself as a biological player in its own right in a vital process: healing. Present at high levels in certain liver, lung or skin cancers, this molecule has been used for decades as a diagnostic marker. However, its natural functions remained largely unknown until now.

Researchers at Arizona State University, affiliated with the Biodesign Center for Biomaterials Innovation and Translation, today reveal a crucial role for SerpinB3 in epithelial tissue regeneration. Published in the journal Proceedings of the National Academy of Sciences (PNAS), their study highlights a hitherto unsuspected endogenous function. This protein actively participates in skin repair. This discovery reshuffles the cards on the link between healing and cancer, two biological processes that have long been studied separately.

A biological redefinition of a protein associated with cancer

Since its discovery in 1977 in cervical cancer tissues, the SerpinB3 protein has constituted a reliable biomarker in the most aggressive epithelial cancers. Present at abnormally high levels in liver, lung, skin or esophageal cancers, it is associated with a poor prognosis, resistance to treatment and a high potential for metastases. However, despite four decades of research in oncology, its endogenous biological function remained mysterious.

It is precisely this lack of understanding that researchers at Arizona State University have filled. By combining transcriptomics, analyzes in vitro
and modeling in vivothey showed that SerpinB3 represents more than a pathological marker. It also plays an active role in normal physiology. It intervenes in response to an injury. The protein is expressed in a controlled manner in the cells of the epidermis during regeneration. This localized response suggests that the body uses SerpinB3 as a lever to quickly restore tissue integrity.

Analysis of injured skin samples revealed highly targeted expression of SerpinB3 in keratinocytes at the migration front. That is to say, those who move forward to close the wound. The expression remains transient and disappears after reconstruction of the epidermis. Unlike the chronic activation observed in tumors. This suggests that cancer hijacks a natural repair function for the purposes of cell dissemination. This functional redefinition repositions SerpinB3 as a central player in tissue homeostasis. And no longer just as an indicator of disruption.

A driving role in cell mobilization and skin reconstruction

The effectiveness of healing relies on the ability of skin cells, mainly keratinocytes, to migrate quickly to the injured area. However, SerpinB3 turns out to constitute a major regulator of this initial phase of the process. In the laboratory, its addition to cell cultures has demonstrated an effect comparable to that of epidermal growth factor (EGF). This is a molecule already well known for stimulating tissue repair.

The mechanism relies on a change in cellular behavior induced by SerpinB3. Keratinocytes lose their cohesion and become more mobile. They adopt an elongated morphology, characteristic of a migratory phenotype. This corresponds to a so-called partial “epithelial-mesenchymal” transition, well documented in cell biology. The cells then express proteins such as fibronectin and reduce their production of E-cadherin, an adhesion marker. By detaching themselves from their neighbors, they can move more easily to cover the wound.

Tests in vitro confirmed this action. Monolayers of human HaCaT cells, treated with the recombinant murine form Serpinb3a, close damaged areas more quickly than controls. These results were consolidated by analyzes in vivo. In mice, wounds treated with Serpinb3a close more quickly. Maximum activity is observed during the first four days after the injury.

The precise localization of the protein in tissues was also mapped. It is concentrated in the most active areas of the epidermis, where keratinocytes advance and multiply.

A structuring action on collagen and extracellular matrices

Beyond cell migration, effective skin repair also involves structured reformation of the dermis. Particularly via collagen remodeling. This process remains essential to regain functional and resistant skin. It requires precise alignment of fibers and reorganization of connective tissue. The researchers demonstrated that SerpinB3 directly influences this key step, independent of fibroblast activation.

Wounds treated with Serpinb3a in mice showed an organization of collagen fibers closer to that observed in intact skin. The orientation of the bundles was more homogeneous, the fibers thicker. Finally, the general structure evoked the “basket weave” pattern characteristic of healthy skin. This reorganization remains crucial to ensure the mechanical strength of the regenerated tissue.

Remarkably, this action does not seem to involve the activation of fibroblasts, as is often the case in classic healing. The α-SMA (alpha-smooth muscle actin) labeling tests, an indicator of fibroblasts activated into myofibroblasts, do not show a significant increase. Likewise, the levels of collagen I synthesized by fibroblasts remain unchanged under the effect of Serpinb3a. This suggests that the improvement in collagen could be orchestrated by the keratinocytes themselves. Or by other immune mediators indirectly influenced by the protein.

Avenues such as the secretion of MMP10 (stromelysin-2) or the release of Relm-α, two molecules involved in the regulation of the extracellular matrix and associated with the regression of scars, are currently being studied. By modulating the tissue environment in a targeted manner, SerpinB3 could thus improve the quality of regeneration, without causing the fibrosing or hypertrophic effects observed with other healing agents.

Therapeutic perspectives for chronic wounds and implications in oncology

Chronic wounds – bedsores, diabetic ulcers, deep burns – affect millions of patients each year. Their treatment mobilizes significant medical resources. Current treatments remain limited and often ineffective. In this context, SerpinB3 is emerging as a serious therapeutic avenue.

As an endogenous molecule, the protein has two advantages. It is naturally tolerated by the body and its effects are localized. The Arizona State University team is already exploring the idea of ​​incorporating SerpinB3 into bioactive dressings capable of stimulating its expression or releasing its recombinant form in a controlled manner. These devices could restart regeneration in tissues where natural signals are deficient.

But this discovery also poses a delicate question. How to use a molecule involved in tumor progression without risking amplifying its deleterious effects? The researchers emphasize one point. It all depends on the activation context. In a wound, SerpinB3 expression remains transient and localized. In a tumor, on the contrary, it appears chronic and dysregulated. It is this nuance that will need to be mastered in future applications.

In terms of cancer, understanding how SerpinB3 promotes cell migration also allows us to imagine targeted inhibitors. Agents capable of blocking its function in metastases. By acting on a point of convergence between healing and tumor invasion, the protein could thus serve as a double lever. Namely: stimulate where the skin fails to repair itself, slow down where the cancer cell escapes. The work continues. The researchers also want to determine whether tissues other than the skin benefit from this natural repair mechanism orchestrated by SerpinB3.

Source: Yaron, JR, et al. (2025). “Squamous cell carcinoma antigen-1/SerpinB3 is an endogenous skin injury response element”. Proceedings of the National Academy of Sciences. doi:10.1073/pnas.2415164122.