miR-138 overexpression is more powerful than hTERT knockdown to potentiate apigenin for apoptosis in neuroblastoma in vitro and in vivo

Abstract

Decrease in expression of the tumor suppressor microRNA-138 (miR-138) correlates well with an increase in telomerase activity in many human cancers. The ability of almost all human cancer cells to grow indefinitely is dependent on presence of telomerase activity. The catalytic component of human telomerase reverse transcriptase (hTERT) regulates telomerase activity in most of the human cancers including malignant neuroblastoma. We observed an indirect increase in the expression of miR-138 after the transfection with hTERT short hairpin RNA (shRNA) plasmid in human malignant neuroblastoma SK-N-DZ and SK-N-BE2 cell lines. Transfection with hTERT shRNA plasmid followed by treatment with the flavonoid apigenin (APG) further increased expression of miR-138. Direct transfection with miR-138 mimic was more powerful than transfection with hTERT shRNA plasmid in potentiating efficacy of APG for decreasing cell viability and colony formation capability of both cell lines. Upregulation of miR-138 was also more effective than down regulation of hTERT in enhancing efficacy of APG for induction of apoptosis in malignant neuroblastoma cells in vitro and in vivo. We delineated that apoptosis occurred with induction of molecular components of the extrinsic and intrinsic pathways in SK-N-DZ and SK-N-BE2 cells both in vitro and in vivo. In conclusion, these results demonstrate that direct miR-138 overexpression is more powerful than hTERT down regulation in enhancing pro-apoptotic effect of APG for controlling growth of human malignant neuroblastoma in cell culture and animal models.

MicroRNA-138 inhibits proliferation, migration and invasion through targeting hTERT in cervical cancer

“…miRNAs can act as either tumor suppressors or promoters and therefore affect tumor development, proliferation, differentiation, migration and invasion (10). The expression of miR-138 is generally low in tumors, including in non-small lung cancer, colorectal cancer, neuroblastoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and hepatocellular carcinoma (14)(15)(16)(17)(18)(19). However, an association between miR-138 expression and cervical cancer has not been previously reported.…”

“…To the best of our knowledge, the present study is the first to demonstrate that miR-138 expression is significantly downregulated in cervical cancer tissues and cell lines, and that low miR-138 expression is negatively associated with advanced FIGO stage and lymph node metastasis. In addition, miR-138 has been previously reported to function as a tumor suppressor in numerous malignancies by targeting various molecules (13)(14)(15)(16)(17)(18)(19). For cervical cancer, a study showed that miR-138 could significantly inhibit HeLa cell migration by targeting required for meiotic nuclear division 5 homolog A (29).…”

“…miR-138, a family of microRNA precursors, has been reported to function as a tumor suppressor in a variety of human cancers, including renal carcinoma (13), non-small lung cancer (14), colorectal cancer (15), neuroblastoma (16), esophageal squamous cell carcinoma (17), nasopharyngeal carcinoma (18) and hepatocellular carcinoma (19). However, the role and the molecular mechanisms of miR-138 in cervical remain unclear.…”

Genetic and Methylation-Induced Loss of miR-181a2/181b2 within chr9q33.3 Facilitates Tumor Growth of Cervical Cancer through the PIK3R3/Akt/FoxO Signaling Pathway

“…Although once considered to represent transcriptional "noise," the posttranscriptional regulator microRNAs (miRNAs) are now recognized to have crucial roles in the pathogenesis of cervical cancer based on the expression of dysreulation (11), such as miR-21, -133b, -138, and so on (12)(13)(14). Of special interest, given that over 50% of miRNAs are located at fragile sites and aberrant regions of chromosomes involved in cancer (15), breakpoint-associated miRNAs might contribute a new insight for considering the causal role of fragile sites in cancer development (16).…”

Inflammation-related and Brain-enriched MicroRNAs Influence the Activation of Microglia Response to In vitro Oxygen-Glucose Deprivation

“…This may reflect that they have a critical role in stopping the activation of microglia. In the research of human cancers, miR-138 was well correlated to an increase in telomerase activity [24] , and was also obviously up-regulated in microglia after 10 minutes of OGD. This indicates that it may have some relationship with microglia's protective role in CNS tumors.…”