STAT3 in cancer: A double edged sword

Abstract

The transcription factor signal transducer and activator of transcription (STAT) 3 is activated downstream of cytokines, growth factors and oncogenes to mediate their functions under both physiological and pathological conditions. In particular, aberrant/unrestrained STAT3 activity is detected in a wide variety of tumors, driving multiple pro-oncogenic functions. For that, STAT3 is widely considered as an oncogene and is the object of intense translational studies. One of the distinctive features of this factor is however, its ability to elicit different and sometimes contrasting effects under different conditions. In particular, STAT3 activities have been shown to be either pro-oncogenic or tumor-suppressive according to the tumor aetiology/mutational landscape, suggesting that the molecular bases underlining its functions are still incompletely understood. Here we discuss some of the properties that may provide the bases to explain STAT3 heterogeneous functions, and in particular how post-translational modifications contribute shaping its sub-cellular localization and activities, the cross talk between these activities and cell metabolic conditions, and finally how its functions can control the behaviour of both tumor and tumor microenvironment cell populations.

Suppressing the metastatic properties of the breast cancer cells using STAT3 decoy oligodeoxynucleotides: A promising approach for eradication of cancer cells by differentiation therapy

“…Transcription factors as unique anticancer targets are the main components of signaling pathways in the cells strongly involved in tumorigenesis. STAT3 is a key transcription factor that plays a pivotal role in tumor cells survival and cancerous ability, so that indicated as an applicable target for cancer targeted therapies (Avalle, Camporeale, Camperi, & Poli, ; Masciocchi, Gelain, Villa, Meneghetti, & Barlocco, ). To further evaluate the role of STAT3 inhibition effect in the stem‐like and high metastatic potential of breast cancer MDA‐MB‐231 cells, we designed a decoy ODN for mimicking STAT3 DNA binding site on human Bcl‐xL gene (based on http://cistrome.org, and http://genome.ucsc.edu database, Score: 1.675, Coordinate: chr20:31664457‐31722853).…”

“…Transcription factors as unique anticancer targets are the main components of signaling pathways in the cells strongly involved in tumorigenesis. STAT3 is a key transcription factor that plays a pivotal role in tumor cells survival and cancerous ability, so that indicated as an applicable target for cancer targeted therapies (Avalle, Camporeale, Camperi, & Poli, 2017;Masciocchi, Gelain, Villa, Meneghetti, & Barlocco, 2011…”

Complex networks of miRNA-transcription factors mediate gene dosage compensation in aneuploid cancer

“…In cancer cells this gene suppresses detection mechanism of the immune system, promotes angiogenesis, invasion and metastasis, deregulates growth (Yue & Turkson, 2009) . STAT3 is an oncogene but recent information indicates that it may also function as a tumor suppressor (Avalle, Camporeale, Camperi, & Poli, 2017) .…”

“…These strategy is promising inasmuch the overexpression of these important transcription factors seem to be more sensitive to blockade of gene dosage compensation when their copy number are more amplified as expected in silico ( Figure 5B) but also suggested by the higher cytotoxicity of colon cancer cells with higher MYC copy numbers upon inhibition of the three miRNAs proposed here to mediate its dosage compensation. Indeed, dysregulated MYC triggers rapid apoptosis (Nilsson & Cleveland, 2003) and STAT3 may function as a tumor suppressor (Avalle et al, 2017). An important prediction of the study of gene dosage compensation in aneuploid yeast was indeed that the phenomenon of dosage compensation occurs at genes that are most toxic when overexpressed (Hose et al, 2015) .…”

STAT3β is a tumor suppressor in acute myeloid leukemia

“…Although STAT3 is most commonly described as an oncogene in cancer, evidence also shows its role as a tumor suppressor. [1][2][3][4][5][6][7][8] This opposing role of STAT3 in cancer depends considerably on its expression as different isoforms. 1,9 Alternative splicing gives rise to full-length STAT3a and truncated STAT3b.…”