Progranulin sustains STAT 3 hyper‐activation and oncogenic function in colorectal cancer cells

Persistent activation of Signal Transducer and Activator of Transcription ( STAT )3 occurs in a high percentage of tumors, including colorectal cancer ( CRC ), thereby contributing to malignant cell proliferation and survival. Although STAT 3 is recognized as an attractive therapeutic target in CRC , conventional approaches aimed at inhibiting its functions have met with several limitations. Moreover, the factors that sustain hyper‐activation of STAT 3 in CRC are not yet fully understood. The identification of tumor‐specific STAT 3 cofactors may facilitate the development of compounds that interfere exclusively with STAT 3 activity in cancer cells. Here, we show that progranulin, a STAT 3 cofactor, is upregulated in human CRC as compared to nontumor tissue/cells and its expression correlates with STAT 3 activation. Progranulin physically interacts with STAT 3 in CRC cells, and its knockdown with a specific antisense oligonucleotide ( ASO ) inhibits STAT 3 activation and restrains the expression of STAT 3‐related oncogenic proteins, thus causing cell cycle arrest and apoptosis. Moreover, progranulin knockdown reduces STAT 3 phosphorylation and cell proliferation induced by tumor‐infiltrating leukocyte ( TIL )‐derived supernatants in CRC cell lines and human CRC explants. These findings indicate that CRC exhibits overexpression of progranulin, and suggest a role for this protein in amplifying the STAT 3 pathway in CRC .