. 2015 Feb 25;16(3):4471–4491. doi: 10.3390/ijms16034471

Table 1.

Contradictory roles of Tpl2 kinase in cancer.

Tumor-Promoting	Tumor-Suppressive
Elevated Tpl2 activity was demonstrated in a number of human cancers and associated with tumorigenesis and cancer progression via activation of the MAPK signaling pathway [14,17,18,19,20,45,47,50,62 ,64,71,72,73,74,75,76,77]. Tpl2 promoted tumorigenesis and cancer progression via the phosphorylation of Pin1 resulting cyclin D1 up-regulation and induced EMT by IL-22/MEK/ERK, JNK/STAT3/AP-1 signaling pathway in breast cancer [62,64,78,79]. Tpl2 facilitated tumor growth by PAUF-mediated MEK/ERK signaling pathway, resulting in increasing expression of pro-tumorigenic cytokines [80]. Inhibiting Tpl2 significantly reduced peritoneal dissemination by inducing endoplasmic reticulum stress and inhibiting EMT and also blocked angiogenesis in gastric cancer [81,82]. Tpl2 transduces PAR1 signals to regulate the expression of MMPs and other secreted molecules both in fibroblasts and tumor cells, and to promote reorganization of the actin cytoskeleton and cell migration [74,83]. Tpl2 kinase contributes to disease progression of clear cell renal cell carcinoma through activated MAPK signaling and cross-talk with CXCL12/CXCR4-directed chemotaxis and chemoinvasion [84]. Elevated Tpl2 activity promoted CRPC growth via activation of MEK/ERK and NF-kB signaling pathway [85]. Tpl2 enhanced tumor progression and metastasis of CRPC through increased cell proliferation, stemness, migration and invasion abilities via activation of FAK/Akt and CXCL12/CXCR4 signaling pathways [86]. Tpl2 mediated TNF-α downstream signaling promoting cell survival, invasion, and angiogenesis [14,55,58,63,87]. Tpl2 plays an important role in promoting IL-17A-induced tumorigenesis in colon cancer, cervical cancer and breast cancer via IL-17A-activated Tpl2 signaling pathway to function upstream of MEK/ERK and JNK/c-Jun [88,89,90]. Tpl2 enhances cancer metastasis through versican/TLR2/6-Tpl2 mediated activation of myeloid cells in the metastatic niche [6,26,91,92,93].	Transduction of anti-proliferative T cell receptor signals and inhibitory effects on transformation of chronically stimulated T cells [75]. Tpl2 ablation significantly enhanced tumor initiation and progression in a chemical-induction mouse skin cancer model via up-regulated NF-κB signaling and MMP activity [94,95,96]. Tpl2 induced resistance to TRAIL induced apoptosis in breast cancer cells, reduced [97]. Tpl2 antagonized cell transformation and survival through JNK dependent up-regulation of NPM required for optimal p53 response to oncogenic or genotoxic stress in urethane-induced lung tumors in mice [98]. Tpl2 ablation promoted colitis-associated cancer through down-regulation of IL-10 and regulatory T-cell numbers in the intestinal mucosa and increased HGF secretion of intestinal myofibroblasts [69,99]. Human effector memory CD8⁺ cytotoxic T cells, which play a major role in adaptive anti-tumor immune responses, are regulated by the IL-12 induced Tpl2/MEK/ERK pathway [100].

Tumor-Promoting

Tumor-Suppressive

Elevated Tpl2 activity was demonstrated in a number of human cancers and associated with tumorigenesis and cancer progression via activation of the MAPK signaling pathway [14,17,18,19,20,45,47,50,62 ,64,71,72,73,74,75,76,77].
Tpl2 promoted tumorigenesis and cancer progression via the phosphorylation of Pin1 resulting cyclin D1 up-regulation and induced EMT by IL-22/MEK/ERK, JNK/STAT3/AP-1 signaling pathway in breast cancer [62,64,78,79].
Tpl2 facilitated tumor growth by PAUF-mediated MEK/ERK signaling pathway, resulting in increasing expression of pro-tumorigenic cytokines [80].
Inhibiting Tpl2 significantly reduced peritoneal dissemination by inducing endoplasmic reticulum stress and inhibiting EMT and also blocked angiogenesis in gastric cancer [81,82].
Tpl2 transduces PAR1 signals to regulate the expression of MMPs and other secreted molecules both in fibroblasts and tumor cells, and to promote reorganization of the actin cytoskeleton and cell migration [74,83].
Tpl2 kinase contributes to disease progression of clear cell renal cell carcinoma through activated MAPK signaling and cross-talk with CXCL12/CXCR4-directed chemotaxis and chemoinvasion [84].
Elevated Tpl2 activity promoted CRPC growth via activation of MEK/ERK and NF-kB signaling pathway [85].
Tpl2 enhanced tumor progression and metastasis of CRPC through increased cell proliferation, stemness, migration and invasion abilities via activation of FAK/Akt and CXCL12/CXCR4 signaling pathways [86].
Tpl2 mediated TNF-α downstream signaling promoting cell survival, invasion, and angiogenesis [14,55,58,63,87].
Tpl2 plays an important role in promoting IL-17A-induced tumorigenesis in colon cancer, cervical cancer and breast cancer via IL-17A-activated Tpl2 signaling pathway to function upstream of MEK/ERK and JNK/c-Jun [88,89,90].
Tpl2 enhances cancer metastasis through versican/TLR2/6-Tpl2 mediated activation of myeloid cells in the metastatic niche [6,26,91,92,93].

Transduction of anti-proliferative T cell receptor signals and inhibitory effects on transformation of chronically stimulated T cells [75].
Tpl2 ablation significantly enhanced tumor initiation and progression in a chemical-induction mouse skin cancer model via up-regulated NF-κB signaling and MMP activity [94,95,96].
Tpl2 induced resistance to TRAIL induced apoptosis in breast cancer cells, reduced [97].
Tpl2 antagonized cell transformation and survival through JNK dependent up-regulation of NPM required for optimal p53 response to oncogenic or genotoxic stress in urethane-induced lung tumors in mice [98].
Tpl2 ablation promoted colitis-associated cancer through down-regulation of IL-10 and regulatory T-cell numbers in the intestinal mucosa and increased HGF secretion of intestinal myofibroblasts [69,99].
Human effector memory CD8⁺ cytotoxic T cells, which play a major role in adaptive anti-tumor immune responses, are regulated by the IL-12 induced Tpl2/MEK/ERK pathway [100].