Loss of transformed phenotype in cancer cells by overexpression of the uteroglobin gene

Abstract

Uteroglobin (UG) is a multifunctional, secreted protein that has receptor-mediated functions. The human UG (hUG) gene is mapped to chromosome 11q12.2-13.1, a region frequently rearranged or deleted in many cancers. Although high levels of hUG expression are characteristic of the mucosal epithelia of many organs, hUG expression is either drastically reduced or totally absent in adenocarcinomas and in viral-transformed epithelial cells derived from the same organs. In agreement with these findings, in an ongoing study to evaluate the effects of aging on UG-knockout mice, 16͞16 animals developed malignant tumors, whereas the wild-type littermates (n ‫؍‬ 25) remained apparently healthy even after 1 1 ⁄2 years. In the present investigation, we sought to determine the effects of induced-expression of hUG in human cancer cells by transfecting several cell lines derived from adenocarcinomas of various organs with an hUG-cDNA construct. We demonstrate that induced hUG expression reverses at least two of the most important characteristics of the transformed phenotype (i.e., anchorage-independent growth on soft agar and extracellular matrix invasion) of only those cancer cells that also express the hUG receptor. Similarly, treatment of the nontransfected, receptor-positive adenocarcinoma cells with purified recombinant hUG yielded identical results. Taken together, these data define receptor-mediated, autocrine and paracrine pathways through which hUG reverses the transformed phenotype of cancer cells and consequently, may have tumor suppressor-like effects.

Lack of an Endogenous Anti-inflammatory Protein in Mice Enhances Colonization of B16F10 Melanoma Cells in the Lungs

“…Animals-UG-KO mice were generated by targeted disruption of the UG gene in embryonic stem cells as described previously (18). Both UG-KO mice and their WT littermates were maintained under germ-free conditions, and all of the experiments were performed according to a protocol approved by the institutional Animal Care and Use Committee.…”

“…It is constitutively expressed in the lungs of all mammals, and targeted disruption of the UG gene in mice (16) increases susceptibility to pulmonary inflammation (17). Moreover, we (18) and others (19) have previously demonstrated that overexpression of UG in cancer cells reverses their transformed phenotype and neoplastic potential. We also demonstrated that UG-knock-out (UG-KO) mice (16) are highly susceptible to lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a carcinogen in cigarette smoke (20).…”

Osteopontin Stimulates Tumor Growth and Activation of Promatrix Metalloproteinase-2 through Nuclear Factor-κB-mediated Induction of Membrane Type 1 Matrix Metalloproteinase in Murine Melanoma Cells

“…The tumor tissues were homogenized; lysed in lysis buffer composed of 50 mM Tris-HCl (pH 7.5) containing 150 mM NaCl, 1% Nonidet P-40, 15 g/ml leupeptin, and 0.5 mM phenylmethylsulfonyl fluoride; and centrifuged at 12,000 ϫ g for 10 min. The clear supernatants were collected, and MMP-2 expression was detected by Western blot analysis (32). Briefly, the sample containing an equal amount of total proteins was resolved by SDS-PAGE.…”

Effect of low-dose mifepristone administration on day 2 after ovulation on transcript profiles in implantation-stage endometrium of rhesus monkeys

“…Higher expression of uteroglobin and follistatin-like 1 in dysregulated non-receptive endometrium is likely to reflect the pro-inflammatory type of endometrial response that has been documented following early luteal mifepristone treatment (Ghosh et al 1996, 1997, Sengupta et al 2003, Miyamae et al 2006. Furthermore, it would be interesting to explore whether so-called tumour suppressor-like action of uteroglobin (Zhang et al 1999) has any bearing on endometrial receptivity and hostility.…”