The branching of complex N-glycans attached to growth factor receptors promotes tumor progression by prolonging growth factor signaling. The addition of the bisecting GlcNAc to complex N-glycans by Mgat3 has varying effects on cell adhesion, cell migration and hepatoma formation. Here we show that Chinese hamster ovary (CHO) cells expressing Mgat3 and the Polyoma Middle T (PyMT) antigen have reduced cell proliferation and growth factor signaling dependent on a galectin lattice. The Mgat3 gene is not expressed in virgin mammary gland but is upregulated during lactation and is expressed in MMTV/PyMT tumors. Mice lacking Mgat3 that cannot transfer the bisecting GlcNAc to N-glycans acquire PyMT-induced mammary tumors more rapidly, have an increased tumor burden, increased migration of tumor cells, and increased early metastasis to lung. Tumors and tumor-derived cells lacking Mgat3 exhibit enhanced signaling through the Ras pathway, and reduced amounts of functionally-glycosylated α-dystroglycan. Constitutive overexpression of an MMTV/Mgat3 transgene inhibits early mammary tumor development and tumor cell migration. Thus the addition of the bisecting GlcNAc to complex Nglycans of mammary tumor cell glycoprotein receptors is a cell-autonomous mechanism serving to retard tumor progression by reducing growth factor signaling.

Lunatic, Manic and Radical Fringe (LFNG, MFNG and RFNG) are N-acetylglucosaminyltransferases that modify Notch receptors and regulate Notch signaling. Loss of LFNG affects thymic T cell development and LFNG and MFNG are required for marginal zone (MZ) B cell development. However, roles for MFNG and RFNG in T cell development, RFNG in B cell development, or Fringes in T and B cell activation, are not identified. Here we show that Lfng/Mfng/Rfng triple knockout (Fng tKO) mice exhibited reduced binding of DLL4 Notch ligand to CD4/CD8 double-negative (DN) T cell progenitors, and reduced expression of NOTCH1 targets Deltex1 and CD25. Fng tKO mice had reduced frequencies of DN1/cKit+ and DN2 T cell progenitors and CD4+CD8+ double positive (DP) T cell precursors, but increased frequencies of CD4+ and CD8+ single positive (SP) T cells in thymus. In spleen, Fng tKO mice had reduced frequencies of CD4+, CD8+, central memory T cells and marginal zone (MZ) B cells, and an increased frequency of effector memory T cells, neutrophils, follicular (Fo) and MZ P B cells. The Fng tKO phenotype was cell-autonomous and largely rescued in mice expressing one allele of a single Fng gene. Stimulation of Fng tKO splenocytes with anti-CD3/CD28 beads or lipopolysaccharide gave reduced proliferation compared to controls, and the generation of activated T cells by concanavalin A or L-PHA was also reduced in Fng tKO mice. Therefore, each Fringe contributes to T and B cell development, and Fringe is required for optimal in vitro stimulation of T and B cells.

The bisecting GlcNAc is transferred to the core mannose residue of complex or hybrid N-glycans on glycoproteins by the β1,4-N-acetylglucosaminyltransferase III (GlcNAcT-III) or MGAT3. The addition of the bisecting GlcNAc confers unique lectin recognition properties to N-glycans. Thus, LEC10 gain-of-function Chinese hamster ovary (CHO) cells selected for the acquisition of ricin resistance, carry N-glycans with a bisecting GlcNAc, which enhances the binding of the erythroagglutinin E-PHA, but reduces the binding of ricin and galectins-1, -3 and -8. The altered interaction with galactose-binding lectins suggests that the bisecting GlcNAc affects N-glycan conformation. LEC10 mutants expressing polyoma middle T antigen (PyMT) exhibit reduced growth factor signaling. Furthermore, PyMT-induced mammary tumors lacking MGAT3, progress more rapidly than tumors with the bisecting GlcNAc on N-glycans of cell surface glycoproteins. In recent years, evidence for a new paradigm of cell growth control has emerged involving regulation of cell surface residency of growth factor and cytokine receptors via interactions and cross-linking of their branched N-glycans with a lattice of galectin(s). Specific cross-linking of glycoprotein receptors in the lattice regulates their endocytosis, leading to effects on growth factor-induced signaling. This review will describe evidence that the bisecting GlcNAc of N-glycans regulates cellular signaling and tumor progression, apparently through modulating N-glycan/galectin interactions.

No abstract

Altered expression of survivin and leukocyte antigen class I (HLA-I) proteins is associated with tumor progression. This study investigated their expressions in clear cell renal cell carcinoma (ccRCC) tissues for association with a clinical significance of ccRCC patients. Ninety ccRCC and 20 normal tissue samples (i.e., control) were immunohistochemically stained for survivin and HLA-I expression for an association with clinicopathological data and survival of ccRCC patients. Survivin protein was expressed in 82.2 % (74/90) of ccRCC tissue samples compared to 0 % in the normal tissues, and HLA-I protein was expressed in 90 % (18/20) of the normal tissues vs. 67.8 % (61/90) in ccRCC samples. Survivin expression was associated with tumor grade, stage, and lymph node metastasis (p = 0.000, p = 0.016, and p = 0.001, respectively). Conversely, lost HLA-I expression did not have any associations with clinicopathological data (p > 0.05). Survivin-negative patients had a higher tumor-free survival rate than patients with survivin expression (p = 0.037). Patients with normal HLA-I levels had a higher tumor-free survival rate than those with reduced HLA-I levels (p = 0.02). The uni- and multivariate analyses indicated that expression of survivin and HLA-I, individually and in combination, was an independent predictor for survival of ccRCC patients. Overexpression of survivin but reduced HLA-I expression is useful in the prediction of tumor-free survival of ccRCC patients.

Accumulated studies showed that numerous microRNAs (miRNAs) were aberrantly expressed in human intrahepatic cholangiocarcinoma (ICC) and contributed to the tumorigenic processes. However, whether miR-129-2-3p is implicated in the ICC initiation and progression is still limited. Here, the results revealed that miR-129-2-3p expression was notably decreased in ICC tissues and cell lines, and that a low miR-129-2-3p expression was obviously associated with distant metastasis and clinical stage. Exogenous miR-129-2-3p expression evidently repressed the proliferative and invasive abilities of ICC cells. Mechanistic studies indicated that Wild-type p53-induced phosphatase 1 (Wip1) was a direct target gene for miR-129-2-3p in ICC cells. Furthermore, silencing Wip1 expression mimicked the suppressive effects of miR-129-2-3p upregulation on ICC cells. Interestingly, reintroduction of Wip1 expression partially abolished the miR-129-2-3p -reduced cell proliferation and invasion in ICC. Moreover, ectopic miR-129-2-3p expression hindered the ICC tumor growth in vivo. To the best of our knowledge, it is the first time to reveal that miR-129-2-3p plays a crucial role in tumor suppression in ICC pathogenesis through directly targeting Wip1. These results will aid in elucidating the roles of miR-129-2-3p in ICC, and suggest that this miRNA may provide a potential target for the treatment of ICC

No abstract

Cholangiocarcinoma (CCA) is a relatively rare malignant tumor originating from the bile duct epithelial cells, and it is one of the malignant tumors with fast growth in incidence and death rate in recent years. CCA carries a very poor prognosis due to a typically late clinical presentation and a poor response to current therapeutics. Currently, surgery is the only possible curative treatment, radiotherapy and chemotherapy also play an important role in slowing down disease progression, while targeted therapy and immunotherapy are changing with each passing day and their combined effect may have great potential for the treatment of CCA; Clinical trials of various treatment options for CCA are also being conducted. This article reviews the different treatment options for CCA and explores the adjuvant treatment for it from a new perspective. In the future, the goal of treatment should be multiple and combined for different CCA patients to achieve individualized programs and improve overall survival.