Progranulin sustains STAT3 hyper-activation and oncogenic function in colorectal cancer cells

Federica Laudisi, Fabio Cherubini, Antonio Di Grazia, Vincenzo Dinallo, Davide Di Fusco, Eleonora Franzè, Angela Ortenzi, Illari Salvatori, Silvia Scaricamazza, Ivan Monteleone, Naoya Sakamoto, Giovanni Monteleone, Carmine Stolfi

Research output: Contribution to journalArticle

Abstract

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 STAT3 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 STAT3 in CRC are not yet fully understood. The identification of tumor-specific STAT3 cofactors may facilitate the development of compounds that interfere exclusively with STAT3 activity in cancer cells. Here, we show that progranulin, a STAT3 cofactor, is upregulated in human CRC as compared to nontumor tissue/cells and its expression correlates with STAT3 activation. Progranulin physically interacts with STAT3 in CRC cells, and its knockdown with a specific antisense oligonucleotide (ASO) inhibits STAT3 activation and restrains the expression of STAT3-related oncogenic proteins, thus causing cell cycle arrest and apoptosis. Moreover, progranulin knockdown reduces STAT3 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 STAT3 pathway in CRC.

Original languageEnglish
JournalMolecular Oncology
DOIs
Publication statusPublished - Jan 1 2019

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Colorectal Neoplasms
Neoplasms
Cell Proliferation
STAT3 Transcription Factor
Antisense Oligonucleotides
Cell Cycle Checkpoints
Cell Survival
Proteins
Leukocytes
Phosphorylation
Apoptosis
Cell Line

Keywords

  • anti-apoptotic proteins
  • antisense oligonucleotide
  • cyclin D1
  • JAK-STAT
  • SHP-2
  • tumor-infiltrating leukocytes

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

Cite this

Laudisi, F., Cherubini, F., Di Grazia, A., Dinallo, V., Di Fusco, D., Franzè, E., ... Stolfi, C. (2019). Progranulin sustains STAT3 hyper-activation and oncogenic function in colorectal cancer cells. Molecular Oncology. https://doi.org/10.1002/1878-0261.12552

Progranulin sustains STAT3 hyper-activation and oncogenic function in colorectal cancer cells. / Laudisi, Federica; Cherubini, Fabio; Di Grazia, Antonio; Dinallo, Vincenzo; Di Fusco, Davide; Franzè, Eleonora; Ortenzi, Angela; Salvatori, Illari; Scaricamazza, Silvia; Monteleone, Ivan; Sakamoto, Naoya; Monteleone, Giovanni; Stolfi, Carmine.

In: Molecular Oncology, 01.01.2019.

Research output: Contribution to journalArticle

Laudisi, F, Cherubini, F, Di Grazia, A, Dinallo, V, Di Fusco, D, Franzè, E, Ortenzi, A, Salvatori, I, Scaricamazza, S, Monteleone, I, Sakamoto, N, Monteleone, G & Stolfi, C 2019, 'Progranulin sustains STAT3 hyper-activation and oncogenic function in colorectal cancer cells', Molecular Oncology. https://doi.org/10.1002/1878-0261.12552
Laudisi, Federica ; Cherubini, Fabio ; Di Grazia, Antonio ; Dinallo, Vincenzo ; Di Fusco, Davide ; Franzè, Eleonora ; Ortenzi, Angela ; Salvatori, Illari ; Scaricamazza, Silvia ; Monteleone, Ivan ; Sakamoto, Naoya ; Monteleone, Giovanni ; Stolfi, Carmine. / Progranulin sustains STAT3 hyper-activation and oncogenic function in colorectal cancer cells. In: Molecular Oncology. 2019.
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