Depletion of tristetraprolin in breast cancer cells increases interleukin-16 expression and promotes tumor infiltration with monocytes/macrophages

Abstract

The RNA-binding protein tristetraprolin (TTP) destabilizes target messenger RNAs (mRNAs) containing AU-rich elements within their 3' untranslated region. Thereby, it controls the expression of multiple inflammatory and tumor-associated transcripts. Moreover, a loss of TTP in tumors predicts disease-associated survival. Although tumor intrinsic functions of TTP have previously been studied, the impact of TTP on the interaction of tumors with their microenvironment remains elusive. As immune cell infiltration into tumors is a critical determinant for tumor progression, this study aimed at determining the influence of tumor cell TTP on the interaction between tumor and immune cells, specifically monocytes (MO)/macrophages (MΦ). Knockdown (k/d) of TTP in T47D breast cancer cells enhanced tumor growth both in vitro and in vivo and increased infiltration of MO into 3D tumor spheroids in vitro and of MΦ into tumor xenografts in vivo. Enhanced migration of MO toward supernatants of TTP-deficient tumor spheroids was determined as the underlying principle. Interestingly, we noticed interleukin-16 (IL-16) mRNA stabilization when TTP was depleted. In line, IL-16 protein levels were elevated in TTP-deficient spheroids and their supernatants as well as in TTP k/d tumor xenografts and critically contributed to the enhanced chemotactic behavior. In summary, we show that the loss of TTP in tumors not only affects tumor cell proliferation and survival but also enhances infiltration of MO/MΦ into the tumors, which is typically associated with poor prognosis. Moreover, we identified IL-16 as a critical TTP-regulated chemotactic factor that contributes to MO/MΦ migration.

Systematic Analysis of AU-Rich Element Expression in Cancer Reveals Common Functional Clusters Regulated by Key RNA-Binding Proteins

“…A deficiency of TTP can lead to the increased growth of cancer cells, because TTP targets those mRNAs involved in cellular proliferation, such as the previously identified cyclin D1 myc, E2F1, and IL6 (32,33) and also the M cell cycle ARE-mRNAs newly identified here. Modulation of TTP in breast and other cancer cells by ectopic expression impacts cellular growth and attenuates tumor xenografts in mice (28,34,35), which is in agreement with the patients' data here.…”

Tristetraprolin Represses Estrogen Receptor α Transactivation in Breast Cancer Cells

“…In breast and prostate cancer, low TTP expression is used as a negative prognostic indicator, and it is associated with rapid tumor progression and poor clinical outcome (52). The role of TTP as a tumor suppressor has been attributed to its ability to promote the decay of mRNAs encoding cell factors involved in inflammation, angiogenesis, tissue invasion, and metastasis (53)(54)(55)(56)(57)(58). However, the results presented in this report have substantially extended the known functions of TTP, suggesting that this protein could act as a tumor suppressor through a different mechanism.…”

Tristetraprolin disables prostate cancer maintenance by impairing proliferation and metabolic function

“…Third, TTP is commonly lost in cervical cancer and this is linked to the destruction of the p53 tumor suppressor, as TTP binds to and destabilizes the mRNA encoding the ubiquitin ligase E6-AP [8]. Fourth, in breast cancer depletion of TTP augments levels of IL-16, which promotes monocyte and macrophage tumor infiltrates and tumor progression [9]. Fifth, low TTP levels in mutant BRAF V600E -driven melanoma triggers increased levels of IL-8 (CXCL8), tumor growth, and angiogenesis [10].…”