Arginine reprograms metabolism in liver cancer via RBM39.

Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.

Toll-Like Receptor 7 Staining in Malignant Epithelial Tumors.

BACKGROUND: As important players of the innate immune system, Toll-like receptors (TLRs) and their role for tumorigenesis have been in the focus of research. In particular TLR7 is an interesting candidate, as TLR7 agonists are broadly used for the treatment of cutaneous tumors. However, data addressing the baseline expression of TLR7 in both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) on the protein level are lacking, while on the genomic level significantly elevated expression of TLR7 in SCC but not in BCC has been demonstrated. AIM: Our aim was to characterize the immunohistochemical staining pattern of TLR7 in SCC and BCC. Besides, we aimed to clarify if, in case of different TLR7 expression between SCC and BCC, TLR7 expression would help to define basosquamous carcinoma (BSC), a tumor entity sharing characteristics of both SCC and BCC. METHODS: We examined histopathological samples from 23 BCC, 4 BSC, and 24 SCC and characterized the expression of TLR7 by immunohistochemistry and immunofluorescence. RESULTS: We found that TLR7 was not expressed by the tumor tissue of SCC, BCC, and BSC, but by inflammatory cells located within the tumoral and/or peritumoral tissue. Whereas the overall expression of TLR7 did not differ between BCC and SCC (30.4% vs. 45.8%, respectively), we found that within the group of SCC, the well-differentiated SCC showed strong tumoral and/or peritumoral immunocellular TLR7 reactivity in contrast to the poorly differentiated SCC (73.33% vs. 11.1%, respectively). Besides, immunofluorescence double staining revealed the expression of TLR7 in immune cells closely interacting with T cells and natural killer cells. CONCLUSIONS: In contrast to genomic data, we did not find a general difference between baseline TLR7 expression of SCC and BCC on the protein level. Nevertheless, the expression of TLR7 by the inflammatory infiltrate associated with SCC may correlate with the degree of differentiation of SCC possibly indicating better outcome.