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Vivek Pant,1 Suman Baral,2 Gita Sayami,3 Prakash Sayami4 1Department of Biochemistry, 2Endocrinology Unit, Department of Medicine, 3Department of Pathology, 4Manmohan Cardiothoracic vascular and transplant Center, Institute of Medicine (IOM), Tribhuvan University Teaching Hospital (TUTH), Kathmandu, Nepal Abstract: Doege–Potter syndrome (DPS), a paraneoplastic syndrome, presents as a hypoinsulinemic hypoglycemia from the ectopic secretion of insulin-like growth factor II from a solitary fibrous tumor which may be intrapleural or extrapleural in origin. We report a case of severe hypoglycemia in a 70-year old female initially admitted for resection of left sided solitary fibrous tumor of pleura. Investigation revealed true hypoglycemia, and DPS was diagnosed. The tumor was completely resected, after which no further hypoglycemic episodes were seen in 2 years follow-up. This is the first case of solitary fibrous tumor of pleura with DPS reported from Nepal. Keywords: insulin-like growth factor II, IGF-II, solitary fibrous tumor, hypoglycemia

PELP1 acts as an estrogen receptor (ER) coactivator that exerts an essential role in the ER's functions. ER coregulators have a critical role in the progression and response to hormonal treatment of estrogen-dependent tumors. We previously demonstrated that, in adrenocortical carcinoma (ACC), ER is upregulated and that estradiol activates the IGF-II/IGF1R signaling pathways defining the role of this functional cross-talk in H295R ACC cell proliferation. The aim of this study was to determine if PELP1 is expressed in ACC and may play a role in promoting the interaction between ER and IGF1R allowing the activation of pathways important for ACC cell growth. The expression of PELP1 was detected byWestern blot analysis in ACC tissues and in H295R cells. H295R cell proliferation decrease was assessed by A3-(4,5-Dimethylthiaoly)-2,5-diphenyltetrazolium bromide (MTT) assay and [3H] thymidine incorporation. PELP1 is expressed in ACC tissues and in H295R cells. Moreover, treatment of H295R with E2 or IGF-II induced a multiprotein complex formation consisting of PELP1, IGF1R, ER , and Src that is involved in ERK1/2 rapid activation. PELP1/ER/IGF1R/c-Src complex identification as part of E2- and IGF-II-dependent signaling in ACC suggests PELP1 is a novel and more efficient potential target to reduce ACC growth. [ABSTRACT FROM AUTHOR]

PELP1 acts as an estrogen receptor (ER) coactivator that exerts an essential role in the ER’s functions. ER coregulators have a critical role in the progression and response to hormonal treatment of estrogen-dependent tumors. We previously demonstrated that, in adrenocortical carcinoma (ACC), ERα is upregulated and that estradiol activates the IGF-II/IGF1R signaling pathways defining the role of this functional cross-talk in H295R ACC cell proliferation. The aim of this study was to determine if PELP1 is expressed in ACC and may play a role in promoting the interaction between ERα and IGF1R allowing the activation of pathways important for ACC cell growth. The expression of PELP1 was detected by Western blot analysis in ACC tissues and in H295R cells. H295R cell proliferation decrease was assessed by A3-(4,5-Dimethylthiaoly)-2,5-diphenyltetrazolium bromide (MTT) assay and [3H] thymidine incorporation. PELP1 is expressed in ACC tissues and in H295R cells. Moreover, treatment of H295R with E2 or IGF-II induced a multiprotein complex formation consisting of PELP1, IGF1R, ERα, and Src that is involved in ERK1/2 rapid activation. PELP1/ER/IGF1R/c-Src complex identification as part of E2- and IGF-II-dependent signaling in ACC suggests PELP1 is a novel and more efficient potential target to reduce ACC growth.

Abstract: The proteoglycan decorin, a key component of the tumor stroma, regulates the action of several tyrosine-kinase receptors, including the EGFR, Met and the IGF-IR. Notably, the action of decorin in regulating the IGF-I system differs between normal and transformed cells. In normal cells, decorin binds with high affinity to both the natural ligand IGF-I and the IGF-I receptor (IGF-IR) and positively regulates IGF-IR activation and downstream signaling. In contrast, in transformed cells, decorin negatively regulates ligand-induced IGF-IR activation, downstream signaling and IGF-IR-dependent biological responses. Whether decorin may bind another member of the IGF-I system, the insulin receptor A isoform (IR-A) and its cognate ligands, insulin, IGF-II and proinsulin, have not been established. Here we show that decorin bound with high affinity insulin and IGF-II and, to a lesser extent, proinsulin and IR-A. We utilized as a cell model system mouse embryonic fibroblasts homozygous for a targeted disruption of the Igf1r gene (designated R− cells) which were stably transfected with a human construct harboring the IR-A isoform of the receptor. Using these R−/IR-A cells, we demonstrate that decorin did not affect ligand-induced phosphorylation of the IR-A but enhanced IR-A downregulation after prolonged IGF-II stimulation without affecting insulin and proinsulin-dependent effects on IR-A stability. In addition, decorin significantly inhibited IGF-II-mediated activation of the Akt pathways, without affecting insulin and proinsulin-dependent signaling. Notably, decorin significantly inhibited IGF-II-mediated cell proliferation of R−/IR-A cells but affected neither insulin- nor proinsulin-dependent mitogenesis. Collectively, these results suggest that decorin differentially regulates the action of IR-A ligands. Decorin preferentially inhibits IGF-II-mediated biological responses but does not affect insulin- or proinsulin-dependent signaling. Thus, decorin loss may contribute to tumor initiation and progression in malignant neoplasms which depend on an IGF-II/IR-A autocrine loop. [Copyright &y& Elsevier]

The prognosis of hepatocellular carcinoma (HCC) remains dismal. Insulin-like growth factor II (IGF-II), a fetal growth factor, is highly expressed during HCC development. We examined serum IGF-II levels and circulating IGF-II messenger RNA (mRNA) expression and analyzed the clinicopathologic characteristics in patients with liver diseases. The higher IGF-II level in the serum of patients with HCC could be correlated with hepatitis B virus infection but not with patient sex, age, tumor size, or α-fetoprotein (AFP) level. Total RNAs were extracted from liver tissues or peripheral blood mononuclear cells, and IGF-II complementary DNA (cDNA) and AFP cDNA were synthesized through random primers and reverse transcriptase; gene fragments were amplified by nested polymerase chain reaction and confirmed by sequencing. The incidence of the hepatic IGF-II gene was 100% in HCC, 54.3% in paracancerous tissues, and none in noncancerous tissues. The incidence rates for circulating IGF-II and AFP genes were 34.3% and 52.7%, respectively, and for both, 61.6% in patients with HCC. They were 100% in cases with extrahepatic metastasis. The IGF-II abnormality associates with HCC, and circulating IGF-II and IGF-II mRNA are useful molecular markers for HCC differential diagnosis and hematogenous metastasis. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to test the expressions of Livin and insulin-like growth factor II (IGF-II) in colorectal cancers and discuss their significance of carcinogenesis and progression in colorectal cancers, to provide a new target and theory basement for cancer therapy. Methods: The expressions of Livin and IGF-II were detected by immunohistochemistry SABC in 60 cases of colorectal cancer and their associated colorectal tissues, and the associations between the expression levels of Livin and IGF-II and clinical pathological characteristics were analyzed. Results: The positive rates of Livin and IGF-II in colorectal carcinomas were 68.33% and 63.33% respectively, higher than those of para-carcinomatous normal tissues and colorectal adenomas. There were no significant correlations between the expressions of Livin, IGF-II in colorectal carcinomas and the patient's age, sex, tumor size and location, while distant metastasis, Dukes stage, histological type, lymph node metastasis, and whether the tumors have received radiotherapy and chemotherapy were significantly correlated with the expressions of Livin, IGF-II in colorectal carcinomas. Conclusion: Livin and IGF-II play important roles in carcinogenesis and progression of colorectal cancer. This study showed obvious correlation between the expressions of Livin and IGF-II in colorectal cancers. It could be used as the reference for further researches. Livin is hopeful to be a new molecular target in cancer therapy. [ABSTRACT FROM AUTHOR]

An intrauterine device (IUD) is one of the most effective reversible contraceptive methods currently available. Women who use IUDs may become pregnant, albeit rarely, and many such women continue to use IUDs. Because it is difficult to remove or it may cause miscarriage. This study measured the changes in human leucocyte antigen-G (HLA-G) and insulin-like growth factor II (IGF-II) levels in the decidua and villi to explore the effect of a copper IUD on embryonic development. A total of 54 samples of decidual and villus tissue were collected from pregnant women with IUDs (27 samples) or without IUDs (27 samples). Hematoxylin-eosin staining was used to identify morphological characteristics. Immunohistochemistry was used to detect HLA-G and IGF-II; the protein expression levels were measured via Western blotting. HLA-G was expressed on the membranes of trophoblasts of villus tissues and the glandular epithelium, and in stromal cells of decidual tissues, in both the IUD and control groups. IGF-II was expressed in the glandular epithelium and cytoplasm of trophoblasts and decidual cells in both groups. Compared to the control group, IGF-II expression was significantly reduced in villus tissues of the IUD group (p < 0.05). The mean sac diameter was significantly positively correlated with IGF-II expression in the villi (p < 0.05). A copper IUD may affect embryonic development by regulating the expression of villus IGF-II. • Women who use IUDs may become pregnant, and may continue to use IUDs • IGF-II is involved in the regulation of several stages of early pregnancy • The copper IUD may affect the development of the embryo by affecting villus IGF-II. [ABSTRACT FROM AUTHOR]

Dehydroepiandrostreone (DHEA) is a neuroactive steroid produced by the inner layer of the adrenal cortex close to the adrenomedullary cells. Chromaffin cell growth and proliferation are under the control of insulin-like growth factor II (IGF-II) and basic fibroblast growth factor (bFGF). The aim of the present study was to examine the role of DHEA on chromaffin cell proliferation induced by IGF-II and bFGF. In our model, DHEA significantly decreased IGF-II-induced proliferation by 48.7%, whereas it did not affect the proliferation induced by bFGF. These data suggest that DHEA exerts a paracrine function in the control of chromaffin cell growth. [ABSTRACT FROM AUTHOR]

Abstract: The aim of these experiments was to study the role of protein kinase A (PKA), cyclin-dependent kinase 2 (CDC2) and insulin-like growth factor II (IGF-II) in the control of ovarian function in domestic fowl, as well as the role of PKA and CDC2 in mediating the effects of IGF-II on the ovary. For this purpose, we studied the influence of an inhibitor of PKA (KT5720; 50ng/ml), a CDC2 blocker (olomoucine; 1μg/ml), IGF-II (0, 1, 10 or 100ng/ml) and their combinations on cultured fragments of chicken ovarian follicular wall. Accumulation of PKA and CDC2 and secretion of progesterone (P4), testosterone (T), estradiol (E2) and arginine–vasotocin (AVT) were evaluated by using SDS-PAGE–Western blotting and RIA/EIA. IGF-II addition to culture medium stimulated T, E2 and AVT secretion and inhibited P4 secretion. These changes were associated with an increase in PKA and a decrease in CDC2 accumulation. The PKA blocker KT5720, when given alone, increased accumulation of PKA and secretion of T and E2, but not AVT and inhibited P4 secretion. The PKA blocker also prevented and even reversed the effects of IGF-II on PKA and steroid hormones secretion, but enhanced the action of IGF-II on AVT. The inhibitor of CDC2, olomoucine, when given alone, suppressed the expression of CDC2 and the secretion of P4 and AVT (but not T and E2). When given together with IGF-II, it augmented IGF-II-induced suppression of CDC2 and reversed the effects of IGF-II on P4 (but not on T, E2 or AVT). These observations demonstrate the involvement of PKA, CDC2 and IGF-II in regulating the secretory activity of avian ovarian cells. Our data also suggest the involvement of PKA in the mediation of IGF-II effects on P4, T, E2 and AVT secretion. CDC2 can mediate the effects of IGF-II on ovarian P4 secretion but not on other hormones. [Copyright &y& Elsevier]

A great majority of adrenocortical tumors are benign, and many adrenocortical carcinomas (ACC) are obviously malignant at presentation. The histopathological diagnosis of ACC is occasionally difficult, particularly with stage I and stage II disease. The prognosis of ACC is generally poor. Surgery is the major treatment, with chemotherapy and radio-therapy being applicable to only restricted patients. The Weiss criteria are useful in diagnosing the common adult type of ACC. Histopathological prognostic factors of ACC have not been fully established because of the rarity of the disease. In this article, we first describe the current histopathological diagnostic and prognostic factors of ACC, highlighting the special types of ACC to which Weiss’s criteria are not fully applicable. These special type tumors include pediatric adrenocortical tumors, oncocytomas, and aldosterone-producing tumors of pure zona glomerulosa type. Then we present three cases with unusual small adrenocortical tumors. One patient had an unequivocal ACC showing metastatic disease. One had a histologically defined ACC with no metastasis or macroscopic invasion. The third was a pediatric patient with a tumor showing a nodule-in-nodule pattern with insulin-like growth factor II expression. [ABSTRACT FROM AUTHOR]