TY - JOUR
T1 - MicroRNA 96 is a post-transcriptional suppressor of anaplastic lymphoma kinase expression
AU - Vishwamitra, Deeksha
AU - Li, Yong
AU - Wilson, Desiree
AU - Manshouri, Roxsan
AU - Curry, Choladda V.
AU - Shi, Bin
AU - Tang, Xi Ming
AU - Sheehan, Andrea M.
AU - Wistuba, Ignacio I.
AU - Shi, Ping
AU - Amin, Hesham M.
N1 - Funding Information:
Supported by grants from the National Cancer Institute ( K08CA114395 and R01CA151533 ), the Physician Scientist Program Award, and a Bridge Funding Grant from The University of Texas MD Anderson Cancer Center (H.M.A.).
PY - 2012/5
Y1 - 2012/5
N2 - Anaplastic lymphoma kinase (ALK) constitutes a part of the oncogenic fusion proteins nucleophosmin-ALK and echinoderm microtubule-associated protein like 4-ALK, which are aberrantly expressed in a subset of T-cell anaplastic large-cell lymphoma and non-small-cell lung cancer, respectively. The expression of mutated, constitutively active ALK also occurs in a subset of neuroblastoma tumors. ALK is believed to play an important role in promoting tumor survival. Nevertheless, the mechanisms underlying the expression of ALK in cancer cells are not completely known. MicroRNA (miR) has been implicated in the regulation of the expression of both oncogenes and tumor suppressor genes. We tested the hypothesis that the expression of ALK could be regulated by miR. Three Internet-based algorithms identified miR-96 to potentially bind with the ALK 3′-untranslated region. Notably, miR-96 levels were markedly decreased in ALK-expressing cancer cell lines and primary human tumors compared with their normal cellular and tissue counterparts. Transfection of the cell lines with miR-96 decreased levels of the different forms of ALK protein, without significant effects on ALK mRNA. Furthermore, miR-96 decreased the phosphorylation of ALK target proteins, including Akt, STAT3, JNK, and type I insulin-like growth factor receptor, and it down-regulated JunB. These effects were associated with reduced proliferation, colony formation, and migration of ALK-expressing cancer cells. These data provide novel evidence that decreases in miR-96 could represent a mechanism underlying the aberrant expression of ALK in cancer cells.
AB - Anaplastic lymphoma kinase (ALK) constitutes a part of the oncogenic fusion proteins nucleophosmin-ALK and echinoderm microtubule-associated protein like 4-ALK, which are aberrantly expressed in a subset of T-cell anaplastic large-cell lymphoma and non-small-cell lung cancer, respectively. The expression of mutated, constitutively active ALK also occurs in a subset of neuroblastoma tumors. ALK is believed to play an important role in promoting tumor survival. Nevertheless, the mechanisms underlying the expression of ALK in cancer cells are not completely known. MicroRNA (miR) has been implicated in the regulation of the expression of both oncogenes and tumor suppressor genes. We tested the hypothesis that the expression of ALK could be regulated by miR. Three Internet-based algorithms identified miR-96 to potentially bind with the ALK 3′-untranslated region. Notably, miR-96 levels were markedly decreased in ALK-expressing cancer cell lines and primary human tumors compared with their normal cellular and tissue counterparts. Transfection of the cell lines with miR-96 decreased levels of the different forms of ALK protein, without significant effects on ALK mRNA. Furthermore, miR-96 decreased the phosphorylation of ALK target proteins, including Akt, STAT3, JNK, and type I insulin-like growth factor receptor, and it down-regulated JunB. These effects were associated with reduced proliferation, colony formation, and migration of ALK-expressing cancer cells. These data provide novel evidence that decreases in miR-96 could represent a mechanism underlying the aberrant expression of ALK in cancer cells.
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U2 - 10.1016/j.ajpath.2012.01.008
DO - 10.1016/j.ajpath.2012.01.008
M3 - Article
C2 - 22414602
AN - SCOPUS:84860231932
SN - 0002-9440
VL - 180
SP - 1772
EP - 1780
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -