Protein Kinase C Epsilon and Genetic Networks in Osteosarcoma Metastasis

Abstract

Osteosarcoma (OS) is the most common primary malignant tumor of the bone, and pulmonary metastasis is the most frequent cause of OS mortality. The aim of this study was to discover and characterize genetic networks differentially expressed in metastatic OS. Expression profiling of OS tumors, and subsequent supervised network analysis, was performed to discover genetic networks differentially activated or organized in metastatic OS compared to localized OS. Broad trends among the profiles of metastatic tumors include aberrant activity of intracellular organization and translation networks, as well as disorganization of metabolic networks. The differentially activated PRKCε-RASGRP3-GNB2 network, which interacts with the disorganized DLG2 hub, was also found to be differentially expressed among OS cell lines with differing metastatic capacity in xenograft models. PRKCε transcript was more abundant in some metastatic OS tumors; however the difference was not significant overall. In functional studies, PRKCε was not found to be involved in migration of M132 OS cells, but its protein expression was induced in M112 OS cells following IGF-1 stimulation.

The molecular mechanism study of insulin on proliferation and differentiation of osteoblasts under high glucose conditions

“…Discs large MAGUK scaffold protein 2 (DLG2, also called PSD‐93) is a tumour suppressor that acts as a scaffold at cell‐cell junctions . It is found that the differentially expressed DLG2 can interact with PRKCε‐RASGRP3‐GNB2 network in osteosarcoma cell lines . In addition, the recurrent somatic mutation of DLG2 was also found in osteosarcoma .…”

“…Moreover, three differentially expressed mRNAs including up‐regulated Krüppel‐like factor 10 (Klf10) and down‐regulated paired box 8 (Pax8) and PR/SET domain 16 (Prdm16) were included in these processes. KLF10 (also called EGR‐alpha, EGRA, TIEG, and TIEG1) is a member of the Krüppel family of transcription factors and plays various roles in cell proliferation, differentiation, bone formation, and mineralization in human osteoblasts . It is indicated that deletion of KLF10 in osteoblasts leads to disorders of canonical and noncanonical Wnt signalling pathways during the course of osteoblasts differentiation .…”

“…20 It is found that the differentially expressed DLG2 can interact with PRKCε-RASGRP3-GNB2 network in osteosarcoma cell lines. 21 In addition, the recurrent somatic mutation of DLG2 was also found in osteosarcoma. 22 Herein, we found that the expression of Avp and Dlg2 was down-regulated in the osteoblast cells treated with insulin.…”

“…25 osteoblasts. 21,26 It is indicated that deletion of KLF10 in osteoblasts leads to disorders of canonical and noncanonical Wnt signalling pathways during the course of osteoblasts differentiation. 27 PAX8, a tissue-specific transcription factor, belongs to the Pairedbox (Pax) gene family.…”

Current Status and Prospects of Targeted Therapy for Osteosarcoma

“…Meanwhile, in investigations of IGF-1R expression, increased expression of IGF-1R was closely associated with malignant metastasis and prognosis of OS, and high expression of IGF-1R in OS patients was associated with poorer prognosis [ 97 ]. In addition, inhibition of growth hormone release in mice by growth shift analogs or growth hormone-releasing hormone antagonists reduces serum IGF-1 levels and inhibits tumor growth, possibly because these compounds reduce IGF-I stimulation and directly affect cell growth [ 98 , 99 ]. However, a phase I clinical trial of long-acting somatostatin analogs in OS patients showed that, although long-acting somatostatin analogs can reduce serum IGF-I levels, no clinical response was observed [ 100 ].…”