Background: De-regulation of microRNA (miRNA) has been extensively investigated in both Hodgkin (HL) and non-Hodgkin lymphomas (NHL), however, little is known about the roles of miRNAs in T-cell lymphoblastic lymphoma (T-LBL). To understand the involvement of miRNAs in the development and treatment of (T-LBL), miRNA profiles were compared between tumor and corresponding non-tumor tissues.

Methods: miRCURY LNA array was used to generate miRNA expressing profile. Real-time quantitative PCR and immunohistochemistry (IHC) were applied to detect the expression of miR-374b, AKT1 and Wnt16 in T-LBL samples. Dual-luciferase reporter assay was conducted to confirm target associations of miR-374b. The tumor suppressive effect of miR-374b was determined by both in-vitro and in-vivo studies.

Results: The expression of 380 miRNAs was evaluated in five human T-LBL tissues and correspondence normal peripheral blood T-cells by microRNA microarrays. The down-regulation of miR-374b was frequently detected in primary T-LBL tissues, which was significantly associated with patients worse overall survival (P<0.001) and increasing risk of recurrence (P=0.012). Functional assays demonstrated that miR-374b could suppress T-NHL cells proliferation in vitro and in vivo. Furthermore, miR-374b could also sensitize cells to both serum starvation- and chemotherapeutic agent-induced apoptosis. Significantly, subsequent investigation characterized two AKT pathway associated molecules, AKT1 and Wnt16, as direct targets of miR-374b and account for the effect of miR-374b in T-NHL cells. Consistently, in tissues of our T-LBL patients, AKT1 and Wnt16 expression was inversely correlated with miR-374b levels, and could also be independent predictors of recurrence and survival of these patients.

Conclusions: Our data highlight the molecular etiology and clinical significance of miR-374b in T-LBL. Targeting miR-374b may represent a new therapeutic strategy to improve the therapy effect and survival for T-LBL patients.

Figure 1:
Figure 1:. Down-regulation of miR-374b is associated with poor prognosis of T-LBL
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Down-regulation of miR-374b is associated with poor prognosis of T-LBL

Figure 1:
Figure 1:. Down-regulation of miR-374b is associated with poor prognosis of T-LBL
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Down-regulation of miR-374b is associated with poor prognosis of T-LBL

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Figure 2:
Figure 2:. ectopic expression of miR-374b suppress T-NHL cells proliferation and sensitize cells to both serum starvation- and chemotherapeutic agent-induced apoptosis
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ectopic expression of miR-374b suppress T-NHL cells proliferation and sensitize cells to both serum starvation- and chemotherapeutic agent-induced apoptosis

Figure 2:
Figure 2:. ectopic expression of miR-374b suppress T-NHL cells proliferation and sensitize cells to both serum starvation- and chemotherapeutic agent-induced apoptosis
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ectopic expression of miR-374b suppress T-NHL cells proliferation and sensitize cells to both serum starvation- and chemotherapeutic agent-induced apoptosis

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Figure 3:
Figure 3:. Wnt16 and AKT1 are direct targets of miR-374b
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Wnt16 and AKT1 are direct targets of miR-374b

Figure 3:
Figure 3:. Wnt16 and AKT1 are direct targets of miR-374b
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Wnt16 and AKT1 are direct targets of miR-374b

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Disclosures

No relevant conflicts of interest to declare.

Topics:
akt1 gene, apoptosis, biological markers, lymphoblastic t-cell lymphoma, micrornas, neoplasms, starvation, hodgkin's disease, luciferases, lymphoma, non-hodgkin

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2014 by The American Society of Hematology
2014
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