Attenuation of Leukemia/Lymphoma-Related Factor Protein Expression Inhibits Glioma Cell Proliferation and Invasion

Abstract

Overexpression of leukemia/lymphoma-related factor (LRF), which is an erythroid myeloid ontogenic factor protein, occurs in different cancers, including glioma. LRF is also reported to have an oncogenic activity in various human cancers. This study investigated the effect of LRF knockdown on the regulation of glioma growth. LRF short hairpin RNA (shRNA) suppressed the expression of LRF protein in a glioma cell line (GL261-EGFP) compared to the negative control vector-transfected glioma cells. LRF knockdown also reduced glioma cell viability and enhanced cisplatin-induced apoptosis in glioma cells. AKT activation and the expression of various cell cycle-related genes were inhibited following LRF knockdown. The effect on growth and migration is related to dose response results of AKT and nuclear factor-kappa B (NF-κB) inhibitors. These data demonstrate that LRF may play a role in glioma progression, suggesting that inhibition of LRF expression using LRF shRNA should be further evaluated as a novel target for the control of glioma.

LRF inhibits p53 expression in colon cancer cells via modulating DAP5 activity

“…Published data indicate that LRF is associated with the pathogenesis of malignant tumours . We wondered if LRF was also expressed in Cca cells.…”

“…Published data indicate that LRF is associated with the pathogenesis of malignant tumours. 14 We wondered if LRF was also expressed in Cca cells. To test this, we analysed human Cca cell lines, the LIM1215 and HCT116 cells, by RT-qPCR and Western blotting.…”

The multi-faceted functioning portrait of LRF/ZBTB7A

“…However, LRF/ ZBTB7A association with cancer progression goes far beyond hematological cancers. After the initial report associating LRF/ ZBTB7A with T cell lymphoblastic lymphoma/leukemia through the suppression of the Arf tumor suppressor ( p19 Arf ) gene and the consequent decrease of p53 activity [38], accumulating evidence further show that LRF/ ZBTB7A is overexpressed in several other human cancers, including non-small cell lung cancer (NSCLC) [40–43], hepatocellular carcinoma [44–48], prostate [49, 50], ovarian [51], breast [52–54] and gastric cancers [55], glioma [56], sarcomas [57, 58], colorectal cancer [59–62], and renal carcinoma [63]. Further elucidation of these oncogenic functions revealed that LRF/ ZBTB7A can influence cancer cell survival and proliferation, apoptosis, invasion and migration/metastasis, traits comprising some of the key biological capabilities required for the multistep development of human cancer, also presented as “hallmarks of cancer” [64].…”

“…These data highlighted not only the diversity of its roles but also their context-dependency. Cell cycle-related genes are frequent targets of LRF/ ZBTB7A [48, 56, 57, 59, 65–67], offering a mechanistic explanation of the factor’s ability to affect cell proliferation. In human hepatocellular carcinoma cell lines, LRF/ ZBTB7A regulates cell cycle progression by either suppressing or promoting the expression of key cell cycle regulators like cyclin-dependent kinase inhibitors 2B, 1B, and 1A ( p15, p27, and p21 genes, respectively), tumor protein p53 ( TP53 ), CYCLIN D1, CYCLIN D3, and cyclin-dependent kinases CDK4 and CDK6.…”