Tpl2 Kinase Impacts Tumor Growth and Metastasis of Clear Cell Renal Cell Carcinoma

Abstract

Due to the innate high metastatic ability of renal cell carcinoma (RCC), many patients with RCC experience local or systemic relapses after surgical resection. A deeper understanding of the molecular pathogenesis underlying advanced RCC is essential for novel innovative therapeutics. Tumor progression locus 2 (Tpl2), upregulated in various tumor types, has been reported to be associated with oncogenesis and metastatic progression via activation of the MAPK signaling pathway. Herein, the relevance of Tpl2 in tumor growth and metastasis of RCC is explored. Inspection of The Cancer Genome Atlas (TCGA) indicated that Tpl2 overexpression was significantly related to the presence of metastases and poor outcome in clear cell RCC (ccRCC), which is the most aggressive subtype of RCC. Moreover, expression of Tpl2 and CXCR4 showed a positive correlation in ccRCC patients. Depletion of Tpl2 by RNAi or activity by a Tpl2 kinase inhibitor in human ccRCC cells remarkably suppressed MAPK pathways and impaired in vitro cell proliferation, clonogenicity, anoikis resistance, migration, and invasion capabilities. Similarly, orthotopic xenograft growth and lung metastasis were significantly inhibited by Tpl2 silencing. Furthermore, Tpl2 knockdown reduced CXCL12-directed chemotaxis and chemoinvasion accompanied with impaired downstream signaling, indicating potential involvement of Tpl2 in CXCR4-mediated metastasis. Taken together, these data indicate that Tpl2 kinase is associated with and contributes to disease progression of ccRCC.

Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy

“…An in vitro study [107] showed that the suppression of MAPK pathways impaired human ccRCC cells' proliferation, clonogenicity, anoikis resistance, migration, and invasion capabilities. Phosphorylated ERK1/2 expression is significantly upregulated in renal clear cell carcinoma when compared to normal cells, in relation to the pathological grade and clinical stage of ccRCC [108].…”

TPL2 kinase regulates the inflammatory milieu of the myeloma niche

“…57 To test the hypothesis that TPL2 is essential for MAM activation and myeloma progression, we crossed Tpl2 2/2 animals 41 to the genetically engineered myeloma model, Vk*MYC. 58,59 Following its initial discovery as an oncogene, 60 Tpl2 has been shown to variably act as a tumor promoter or suppressor gene in various models of solid tumors, [61][62][63][64][65][66][67][68][69][70][71] Figure 4C). By contrast, the rates of apoptosis (cleaved caspase 3 positivity) in CD138 1 cells from tumor-matched animals were low and not significantly different between the 2 genotypes ( Figure 4D).…”

Interference with Tim-3 protein expression attenuates the invasion of clear cell renal cell carcinoma and aggravates anoikis

“…Therefore, anoikis resistance is critical for tumor metastasis. Previous research has reported certain factors that modulate anoikis sensitivity and resistance in ccRCC, including histone deacetylase inhibitors (18), tumor progression locus 2 kinase (19), and HMGA1 (20). Further mechanisms of anoikis sensitivity and resistance in ccRCC remain unknown.…”