Molecular mechanism, regulation, and therapeutic targeting of the STAT3 signaling pathway in esophageal cancer (Review).

ABSTRACT

Esophageal cancer (EC) is the seventh most common cancer globally, and the overall 5­year survival rate is only 20%. Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in EC, and its activation is associated with a poor prognosis. STAT3 can be activated by canonical pathways such as the JAK/STAT3 pathway as well as non­canonical pathways including the Wnt/STAT3 and COX2/PGE2/STAT3 pathways. Activated STAT3, present as phosphorylated STAT3 (p­STAT3), can be transported into the nucleus to regulate downstream genes, including VEGF, cyclin D1, Bcl­xL, and matrix metalloproteinases (MMPs), to promote cancer cell proliferation and induce resistance to therapy. Non­coding RNAs, including microRNAs (miRNAs/miRs), circular RNAs (circRNAs), and long non­coding RNAs (lncRNAs), play a vital role in regulating the STAT3 signaling pathway in EC. Several miRNAs promote or suppress the function of STAT3 in EC, while lncRNAs and circRNAs primarily promote the effects of STAT3 and the progression of cancer. Additionally, various drugs and natural compounds can target STAT3 to suppress the malignant behavior of EC cells, providing novel insights into potential EC therapies.