Thioredoxin Interacting Protein (TXNIP) Is Differentially Expressed in Human Tumor Samples but Is Absent in Human Tumor Cell Line Xenografts: Implications for Its Use as an Immunosurveillance Marker

SIMPLE SUMMARY: The metabolic protein TXNIP plays a crucial role in various cellular processes. Abnormal TXNIP levels are notable, e.g., in type II diabetes, cardiovascular diseases, and tumors. Using immunohistochemical staining for TXNIP in different tumor entities, we give new insights of TXNIP expression on the protein level. In human tumors, staining intensity inversely correlated with aggressiveness of the tumor entity. In contrast, human tumor cell lines grown in mice (xenografts), consistently revealed no staining. Hence, loss of TXNIP suggests a critical role for the development of tumors in xenografts. Furthermore, we investigated TXNIP staining of immunocompetent cells in the proximity of the xenograft tumor tissue. Our findings demonstrate that TXNIP downregulation is a common feature in human tumor xenograft models. Subsequently, TXNIP expression might be used to monitor the functional state of tumor-infiltrating leukocytes in tissue sections and may help to predict response to modern immune therapy. ABSTRACT: Thioredoxin interacting protein (TXNIP) is a metabolic protein critically involved in redox homeostasis and has been proposed as a tumor suppressor gene in a variety of malignancies. Accordingly, TXNIP is downregulated in breast, bladder, and gastric cancer and in tumor transplant models TXNIP overexpression inhibits growth and metastasis. As TXNIP protein expression has only been investigated in few malignancies, we employed immunohistochemical detection in a large multi-tumor tissue microarray consisting of 2,824 samples from 94 different tumor entities. In general, TXNIP protein was present only in a small proportion of primary tumor samples and in these cases was differently expressed depending on tumor stage and subtype (e.g., renal cell carcinoma, thyroid cancer, breast cancer, and ductal pancreatic cancer). Further, TXNIP protein expression was determined in primary mouse xenograft tumors derived from human cancer cell lines and was immunohistochemically absent in all xenograft tumors investigated. Intriguingly, TXNIP expression became gradually lower in the proximity of the primary tumor tissue and was absent in leukocytes directly adjacent to tumor tissue. In conclusion, these findings suggest that TXNIP downregulation is as a common feature in human tumor xenograft models and that intra-tumoral leukocytes down-regulate TXNIP. Hence TXNIP expression might be used to monitor the functional state of tumor-infiltrating leukocytes in tissue sections.