Lycorine hydrochloride Suppresses the Proliferation and Invasion of Esophageal Cancer by Targeting TRIM22 and Inhibiting the JAK2/STAT3 and Erk Pathways

Background: Tumor metastasis and poor drug efficacy are two of the most common causes of therapeutic failure in Cancer patients. The underlying molecular mechanism requires further exploration, and novel effective curative strategies are urgently needed. Nature is a rich source of novel drugs, and Lycorine hydrochloride (Lyc.HCL) is a natural alkaloid with tremendous therapeutic potential. However, the molecular mechanisms of its antitumor activity are still unknown. In the current study, we investigated the effects and mechanisms of Lyc.HCL against esophageal squamous cell carcinomas (ESCCs), which pose serious threats to human life.

Methods: An MTS assay and a clone formation assay were used to assess the viability of ESCC cell lines after Lyc.HCL treatment in vitro. Apoptosis and cell cycle regulation were analyzed using flow cytometry. Wound healing and Transwell assays were used to analyze cell migration, while invasion was analyzed using the Matrigel Transwell assay. We detected the expression of tripartite motif-containing 22 (TRIM22) through immunohistochemistry and Western blotting. A docking experiment was performed to explore the targets of Lyc.HCL. The expression levels of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/extracellular signal-regulated kinase (ERK) pathway components were detected through Western blotting. A rescue experiment was performed to determine the potential role of TRIM22. In addition, we explored the in vivo anti-ESCC effects and mechanism of Lyc.HCL by using it to treat tumor-bearing mice.

Results: The Lyc.HCL treatment was found to inhibit esophageal squamous cell carcinoma cell proliferation both in vitro and in vivo by blocking the cell cycle at the G2 phase, inhibiting cell migration and invasion. We found that the TRIM22 protein was highly expressed in ESCCs but not in normal esophageal tissue. Lyc.HCL directly targeted TRIM22, decreasing the expression of TRIM22 and the JAK2/STAT3 and ERK signaling pathways, both in vitro and in vivo. Using animal experiments, we observed that the depletion of TRIM22 delayed tumor growth, but this effect was significantly reversed upon TRIM22 overexpression.

Conclusions: Taken together, these findings demonstrate that Lyc.HCL can effectively suppress ESCC both in vitro and in vivo by targeting TRIM22 and regulating the JAK2/STAT3 and ERK pathways. These results suggest that Lyc.HCL may serve as a potential novel therapeutic for ESCC, with TRIM22 emerging as a promising target for treatment.

Lycorine hydrochloride; TRIM22; esophageal squamous cell carcinomas; metastasis; proliferation.