Defective Expression of Prohormone Convertase 4 and Enhanced Expression of Insulin-like Growth Factor II by Pleural Solitary Fibrous Tumor Causing Hypoglycemia

Abstract

Abstract.A 75-year-old man was admitted to our hospital because of unconsciousness. His plasma glucose was very low, but his serum levels of insulin and IGF-I were also low. He was found to have a giant solitary pleural tumor, which was completely resected, after which his hypoglycemia ameliorated postoperatively. Histologically, the tumor was consistent with the pathological diagnosis of a solitary fibrous tumor derived from the pleura. Immunohistochemical study revealed positive immunostaining for IGF-II in tumor cells. The presence of high molecular weight (HMW) form of IGF-II in the tumor tissue and patient's serum was confirmed by Western blot analysis. Steady-state mRNA levels of IGF-II and prohormone convertases (PC) 4, a potential protease responsible for IGF-II processing, as determined by RT-PCR were about 14-fold greater and 5-fold less in the tumor tissue than those in normal placental tissue, respectively. Therefore, it is suggested that biologically active, unprocessed HMW form of IGF-II generated from the impaired processing of IGF-II precursor by the defective PC4 expression in the tumor was responsible for the non-islet cell tumor hypoglycemia (NICTH) in the present case.

Insulin-like growth factor 2 rescues aging-related memory loss in rats

“…Further, PC2 together with PC1 generates insulin through endoproteolytic processing of preproinsulin (Bailyes et al, 1991; Seidah and Prat, 2012; Steiner et al, 1996). IGF-2 has been found to be processed by PC4 in other tissues (Qiu et al, 2005; Tani et al, 2008); in fact, this enzyme subtype is exclusively expressed in testicular germ cells in males and in the placenta and ovary in females (Gyamera-Acheampong and Mbikay, 2009; Seidah and Prat, 2012), and therefore it is unlikely that PC4 is responsible for IGF-2 processing in the brain. We suggest that in the brain PC2 and/or PC2 together with PC1 process precursor forms of IGF-2 into mature IGF-2, and identifying approaches that reduce PC2 deficits may also be an interesting and novel avenue for developing therapies against cognitive impairments.…”

IGF2 and cancer

“…Secondly, the quantity of pro-IGF2 produced may overwhelm the proteolytic capacity of the tumour cells (Zapf 1993). In support of this, defective PC4 expression has been reported in a tumour causing NICTH (Tani et al 2008). Increased serum concentrations of the E-domain have also been observed in patients with NICTH (Daughaday & Trivedi 1992b).…”

Growth hormone therapy in non-islet cell tumor mediated hypoglycemia associated with metastatic lung adenocarcinoma

“…These molecules are formed due to abnormal processing of an IGF-2 precursor in tumors with aberrant IGF-2 gene transcription and gene expression [8,9]. This disrupts the normal creation of ternary complexes of IGF-2, IGF-binding protein 3 (IGFBP-3), and acid labile subunit (ALS).…”