A new function of the IB protein has been identified that is key in the development of squamous-cell carcinoma, a type of skin cancer. The study provides a new tool for the diagnosis of the disease. In the future, this research will enable the identification of novel therapeutic targets to treat this type of cancer.

“In this study we identified a new function of a protein that directly regulates the activity of the genes involved in cell differentiation and in the development of cancer” explained study coordinator Dr. Lluís Espinosa of the Hospital del Mar Medical Research Institute in Barcelona, Spain.

Until now, the only known function of the IB protein was in the cytoplasm, where it inhibits the NF-B factor, a protein complex that is involved in the immune response. This study has found that a different form of IB exists in the nucleus of keratinocytes (typical skin cells) and also in the nucleus of fibroblasts. This different form results from IB binding to the molecule known as SUMO (small ubiquitin-like modifier), which leads to the SUMO-IB protein complex. This complex had been previously observed by other groups, but its function was unknown.

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During the study, the authors analyzed a cohort of 112 patient samples with urogenital skin squamous-cell carcinoma at different stages of tumor progression. Results showed that in samples with invasive tumors, IB disappeared from the nucleus, which indicated that nuclear IB was lost and accumulated in the cytoplasm as tumors progressed.

The finding of this new function of IB in the cell nucleus represents a change in the paradigm of this field and could even entail a reinterpretation of some previously published studies.

Every year, more than 250,000 new cases of squamous-cell skin cancer are diagnosed. This is the second most common type of skin cancer. It develops in the squamous cells that form the upper layers of the skin. Until now, there were no good clinical or histological markers to predict metastasis in this type of tumor.

“Although it still has to be validated in a sufficient number of patients, the detection of this protein in skin lesions could serve as a diagnosis tool and to predict the prognosis of squamous-cell carcinoma” explained co-researcher Agustí Toll, a dermatologist at the Hospital del Mar.

Besides being a possible biomarker for squamous-cell carcinoma prognosis, the identification of the mechanisms regulating the aggressive behavior of skin tumors could have a therapeutic use. When metastasis occurs, the prognosis of patients with these tumors is generally poor and current treatments (surgery, radiotherapy and chemotherapy) are linked to severe side effects, especially among elderly patients.

“This discovery could have a very significant impact on the treatment of this type of cancer when we identify drugs that revert the loss of nuclear IB that is observed in squamous-cell carcinoma,” said Espinosa.