Epimedium inhibits the survival and migration of basal cell carcinoma cells through the Hedgehog signaling pathway
Basal cell carcinoma accounts for approximately 80% of non melanoma skin cancers and is the most common cancer worldwide. Most basal cell carcinoma can be cured by surgery, but for advanced or progressive basal cell carcinoma, surgery and/or radiation therapy may be inadequate and may even cause significant loss of function or appearance. Although platinum based chemotherapy drugs have significant anti-tumor activity, there is no significant change in the survival rate of patients. Therefore, it is necessary to seek a new treatment method that can improve the prognosis of basal cell carcinoma. Basal cell carcinoma originates from the follicular epidermis or basal keratinocytes of hair follicles. In 95% of sporadic basal cell carcinomas, the Hedgehog (Hh) signaling pathway is abnormally activated. A large amount of research data has shown that Hh signaling pathway inhibitors are highly effective treatment options for refractory and inoperable basal cell carcinoma patients, but it is also common to stop treatment due to adverse drug events. Therefore, developing a novel safe and effective inhibitor of the Hh signaling pathway will significantly improve the current and future therapeutic prospects for basal cell carcinoma. Icaritin is the main active monomeric component of Epimedium, a plant belonging to the Epimedium genus in the Berberidaceae family. In recent years, the anti-tumor effect of icariin has been widely studied, which can inhibit various malignant tumor activities such as cervical cancer, esophageal cancer, melanoma, etc. through different signaling pathways and cell targets. Among them, the Hh signaling pathway plays an important role in the inhibition of proliferation, migration, and invasion of esophageal cancer stem cells by icariin. This study will focus on exploring the anti basal cell carcinoma activity of icariin and its relationship with the Hh signaling pathway, in order to provide new potential drugs for the treatment of basal cell carcinoma.

 

 

The Hh signaling pathway is involved in various biological behaviors such as initiation, migration, and apoptosis of tumor tissues, and is associated with the formation and development of up to one-third of malignant tumors. Hedgehog protein is encoded by at least three genes in vertebrates: Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh). Shh is widely expressed in the skin, nervous system, and digestive tract, acting on two cell membrane receptors, Patched (Ptc) and Smothened (Smo). Under normal physiological conditions, Hh ligands are often absent, and Ptc binds to Smo, inhibiting Smo protein activity and thereby preventing downstream glioma associated oncogene (Gli) transcription factors (Gli1, GliI2, and Gli3) from transferring into the nucleus. When Hh protein binds to Ptc, the inhibition of Smo is released, allowing the full-length Gli protein to enter the nucleus and activate downstream target gene transcription. Research has shown that up to 95% of basal cell carcinomas exhibit abnormal activation of the Hh signaling pathway, with approximately 67% showing Ptc deficiency and 10% showing Smo mutations, leading to Gli entering the nucleus and promoting cell division and tumor formation. Therefore, targeted inhibition of the Hh signaling pathway may effectively suppress the development of basal cell carcinoma without significant effects on normal tissue cells.
Epimedium is often used as a nourishing and aphrodisiac in traditional Asian medicine, with a wide range of therapeutic abilities. Numerous in vivo and in vitro studies have shown that icariin has a wide range of anti-tumor activities, acting through various mechanisms such as apoptosis, cell cycle regulation, anti angiogenesis, anti metastasis, and immune regulation. Among them, inhibiting the Hh signaling pathway is the main mechanism by which icariin inhibits esophageal cancer cells. This study found that icariin has a broad inhibitory effect on Hh signaling pathway related factors (Hedgehog, Smo, Gli1) in basal cell carcinoma A431 cells, while mediating cell apoptosis and inhibiting its migration. This suggests that icariin may exert anti basal cell carcinoma effects by inhibiting the Hh signaling pathway.
Gli is a core member of the Hh signaling pathway, and its downstream target genes include pathway members Ptch1, Ptch2, Gli1, as well as tumor cell apoptosis regulator Bcl-2, cell cycle regulator CCND2, and cell metastasis related factors. MMP-9 is currently one of the most widely studied matrix metalloproteinases, which can cleave various extracellular matrix proteins, regulate extracellular matrix remodeling, and is closely related to tumor invasion, metastasis, and angiogenesis. It is highly expressed in tumors such as liver cancer, oral squamous cell carcinoma, and neuroblastoma and is closely related to the Hh signaling pathway. In order to further elucidate the relationship between the inhibitory effect of icariin on A431 cells and the Hh signaling pathway, this study used GANT 61 to inhibit Gli and achieve the effect of blocking the Hh signaling pathway. The results showed that the expression of Gli1, Bcl-2, and MMP-9 was significantly down regulated, while Bax was significantly up-regulated, and cell apoptosis and migration inhibition were observed. Epimedium has the same effect on regulating the above cytokines and behaviors, but when the Hh signaling pathway is inhibited, icariin loses its regulatory effect on Bcl-2 and Bax, only slightly enhances its inhibitory effect on MMP-9, and cell apoptosis and migration did not show significant changes. This indicates that icariin did not significantly act on A431 cells through other signaling pathways, but its regulation of MMP-9 may have other signaling pathways, which still need further investigation. Research. Therefore, it can be considered that icariin may mainly inhibit the Hh signaling pathway, promote the expression of apoptosis related factors, mediate apoptosis of basal cell carcinoma cells, and downregulate the expression of MMP-9, thereby inhibiting the migration of basal cell carcinoma cells.
In summary, this study indicates that icariin can inhibit the survival and migration ability of basal cell carcinoma cells by suppressing the Hh signaling pathway, providing new ideas and strategies for its use as a targeted or adjuvant therapy for the treatment of basal cell carcinoma.