Mycosis fungoides (MF) is the most common variant of primary cutaneous T‐cell lymphoma, and decreased forkhead box P3 (FoxP3) expression has been reported in MF late stages. Hypoxia‐inducible factor 1 alpha (HIF‐1α) may regulate FoxP3 expression; however, it is unknown whether HIF‐1α is expressed in the CD4+ T cells of MF patients and how it could affect the expression of FoxP3. Therefore, we evaluated the expression of HIF‐1α and FoxP3 in CD4+ T cells obtained from the skin lesions of MF patients. We found increased cell proliferation and an increase in CD4+ T cells with an aberrant phenotype among early stage MF patients. HIF‐1α was overexpressed in these CD4+ T cells. In addition, we found a decrease in the percentage of FoxP3+ cells both in the skin of MF patients, when compared with control skin samples, and with disease progression. In addition, a negative correlation was established between HIF‐1α and FoxP3 expression. Skin HIF‐1α expression in MF patients correlated with the extent of the affected area and increased with the disease progression. Finally, we showed that ex vivo inhibition of HIF‐1α degradation increases the percentage of FoxP3+ T cells in skin lesions. Our results suggest that overexpression of HIF‐1α affects the levels of FoxP3 in MF patients, which could have relevant implications in terms of disease outcome.

These results suggest that a significant mRNA level of MDR1 gene was intrinsically present in STS before exposure to chemotherapeutic drugs, suggesting that MDR1 may be important contributors of innate chemoresistance of this tumor type.

The 5-year relative survival rate estimate of treated patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) is ∼50% since they generally present with tumor progression, relapse, metastasis, and/or chemoresistance. The expression of cytochrome P450 (CYP) enzymes in malignancies can affect the pharmacology of drugs commonly used in chemotherapy or confer susceptibility to development of chemical carcinogenesis; in addition, their specific tumor expression can be used as a therapeutic target. Using qPCR and Western blot assays, the expression of CYP1B1, CYP2E1, CYP3A4, and CYP3A5 were analyzed in a cohort of tumor tissue paired with non-malignant adjacent tissue of patients with NRSTS. The mRNA and protein expression of CYP1B1, CYP2E1, and CYP3A4 were significantly increased in tumor tissue. We propose that the expression of these isoforms is related to carcinogenesis and chemoresistance frequently observed in these neoplasms.

Orphan cytochromes P450 (CYP) are enzymes whose biological functions and substrates are unknown. However, the use of new experimental strategies has allowed obtaining more information about their relevance in the metabolism of endogenous and exogenous compounds. Likewise, the modulation of their expression and activity has been associated with pathogenesis and prognosis in different diseases. In this work, we review the regulatory pathways and the possible role of orphan CYP to provide evidence that allow us to stop considering some of them as orphan enzymes and to propose them as possible therapeutic targets in the design of new strategies for the treatment of diseases associated with CYP-mediated metabolism.