Hypoxia is a feature of solid tumors. Most tumors are at least partially hypoxic. This hypoxic environment plays a critical role in promoting resistance to anticancer drugs. PHLPP, a novel family of Ser/Thr protein phosphatases, functions as a tumor suppressor in colon cancers. Here, we show that the expression of both PHLPP isoforms is negatively regulated by hypoxia/anoxia in colon cancer cells. Interestingly, a hypoxia-induced decrease of PHLPP expression is attenuated by knocking down HIF1␣ but not HIF2␣. Whereas the mRNA levels of PHLPP are not significantly altered by oxygen deprivation, the reduction of PHLPP expression is caused by decreased protein translation downstream of mTOR and increased degradation. Specifically, hypoxiainduced downregulation of PHLPP is partially rescued in TSC2 or 4E-BP1 knockdown cells as the result of elevated mTOR activity and protein synthesis. Moreover, oxygen deprivation destabilizes PHLPP protein by decreasing the expression of USP46, a deubiquitinase of PHLPP. Functionally, downregulation of PHLPP contributes to hypoxia-induced chemoresistance in colon cancer cells. Taken together, we have identified hypoxia as a novel mechanism by which PHLPP is downregulated in colon cancer, and the expression of PHLPP may serve as a biomarker for better understanding of chemoresistance in cancer treatment. Hypoxia is a condition commonly occurring in most solid tumors. Numerous studies have demonstrated that hypoxia plays a pivotal role in tumor progression and metastasis and is often associated with increased malignancy and poor prognosis (1, 2). Serving as the primary modulators of hypoxic stress, hypoxia-inducible factors (HIFs) are rapidly induced in response to oxygen deprivation to regulate the expression of genes that facilitate adaptation to hypoxic conditions (2, 3). The HIF transcription factors are heterodimers consisting of an O 2 -sensitive ␣ subunit and a stable ␤ subunit. There are three isoforms of mammalian HIF␣, of which HIF1␣ and HIF2␣ are the most structurally similar and best characterized (3). Under normoxic condition, HIFs are modified at two conserved proline residues by prolyl hydroxylase domain proteins (PHDs; consisting of PHD1, PHD2, and PHD3). The modified HIFs are subsequently recognized and ubiquitinated by an E3 ligase, the von Hippel-Lindau (VHL) protein, resulting in the degradation of HIF proteins via the proteasome pathway. Under hypoxic conditions, the hydroxylase activity of PHDs is inhibited, and stabilized HIF transcription factors can translocate to the nucleus and regulate the transcription of hypoxia-associated genes (3-5).Previous studies have shown that hypoxia inhibits mTOR and cap-dependent protein translation via a TSC2-dependent mechanism upon the induction of REDD1 (6, 7). mTOR is an evolutionarily conserved serine/threonine protein kinase that functions in two distinct complexes, mTORC1 and mTORC2, in cells. mTORC1 serves as a nutrient and energy sensor by controlling protein translation through phosphorylation of 4E-BP1 and S6K1 (8)....

10046 Background: Malignant tumors may evade immunological surveillance by an active downregulation of T cell activation by PD-1 (programmed death 1)/ PDL-1 signaling. This would result in a decreased immune response, thus, promoting tumor growth. Methods: We analyzed the expression of PD-1/PDL-1 genes, cytokines, and T cell subpopulations in tumor tissues of 81 consecutive patients who underwent surgery for primary colorectal cancer according to their UICC stage. Expression of PD-1/PDL-1, T cell subpopulations, and cytokines in tumor tissues were assessed using immunostaining, immunofluorescence, and Real Time PCR. Results: PDL-1 expression on tumor cells was significantly increased, whereas PD-1 expression on tumor cells was decreased at UICC stage III/IV. However, PD-1 expression on infiltrating CD4+ T cells was detectable in patients with advanced tumors whereas PDL-1 expression on CD4+ cells was particularly found at early stages. More regulatory T cells (CD4+CD25+CTLA-4+Foxp3+) were observed in tumors of stage III/IV patients compared to early stages. In addition, a remarkably increased amount of IL-10 was observed in the tumors of UICC III/IV patients. High expression of TGF-ß receptor II in tumors correlated with a progressive course of the disease and tumor relapses, i.e. TGF-ß RII in early tumor stages was indicative for early tumor progress. Conclusions: Our findings indicate that PDL-1 plays a key role during tumor progression and that regulatory T cells are involved in the process of evasion from immune surveillance. The elevated PDL-1 expression on T cells at early tumor stages suggests that PD1/PDL-1 interaction mediates inhibitory signals between T cells enabling the tumor to progress. PDL-1 blockade may prove to be a valuable approach for cancer immunotherapy. No significant financial relationships to disclose.

Advances in the medical treatment of colorectal cancer patients have resulted in considerable improvements through the introduction of new cytotoxic drugs. The significant progress in molecular and tumour biology has produced a great number of targeted, tumour-specific, monoclonal antibodies that are now in various stages of clinical development. Two of these antibodies, cetuximab (Erbitux) und bevacizumab (Avastin), directed against the epidermal growth factor receptor (EGFR) and the vascular epithelial growth factor (VEGF), respectively, have recently been approved for use in metastatic colorectal cancer. The combination of well-known and newly developed cytotoxic agents with monoclonal antibodies makes the medical treatment of colorectal cancer patients considerably more complex, but also provides additional therapeutic strategies for patients in advanced stages of disease.

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