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.