The role of the WWOX gene in leukemia and its mechanisms of action

Abstract

Abstract. The WW domain-containing oxidoreductase (WWOX) gene which encompasses the common human fragile site FRA16D has been proposed as a putative tumor suppressor gene, and loss of WWOX expression has been found in several types of solid cancer. As the role of WWOX in human leukemia has not yet been fully elucidated, the present study examined the expression of WWOX in patients with different types of leukemia as well as in leukemia-derived cell lines. Based on the data, WWOX mRNA (WWOX) and protein (Wwox) were significantly reduced or absent in the leukemia patients as well as in the cell lines. In addition, a recombinant expression vector, pGC-FU-WWOX, was constructed and transfected WWOX cDNA into Jurkat cells (acute T-lymphoblastic leukemia) and K562 cells (chronic myeloid leukemia in erythroid crisis) which all lack endogenous Wwox. In vitro experiments indicated that restoration of Wwox in Jurkat and K562 cells significantly suppressed proliferation and colony formation. Of note, apoptosis was also induced by Wwox restoration. Furthermore, we traced the mechanisms underlying this process and found that Wwox restoration could trigger the mitochondrial pathway in leukemia. Our data provide evidence that WWOX exerts a role as a tumor suppressor gene in leukemia, possibly by inhibiting proliferation and promoting apoptosis via the mitochondrial pathway.

Reduced expression of the WW domain-containing oxidoreductase in human hematopoietic malignancies

“…Similarly, the aberration or absence of WWOX/WWOX expression in primary hematopoietic malignancies has also been reported (11)(12)(13)(14)(15)(16). A recently published study detected the expression of WWOX/WWOX in a small cohort of 38 primary leukemia patients and observed low expression levels (14). Chen et al (13) recently validated the expression of WWOX in ALL, and observed that the mRNA expression of WWOX, fragile histidine triad and tumor protein p73 was significantly lower in the ALL samples compared with the controls.…”

“…The role of WWOX/WWOX in leukemia has also been reported, suggesting that WWOX may exert antineoplastic activity in human hematopoietic malignancies (11)(12)(13)(14)(15)(16). Our previous studies have demonstrated that WWOX exerts a role as an tumor suppressor gene in leukemia, inhibiting cell proliferation and promoting apoptosis via binding with p73 and triggering of the mitochondrial pathway (14,15).…”

“…The bulk of the data documented have shown that the expression of WWOX/WWOX was lost or reduced in various types of solid cancers (2)(3)(4)(5)(6)(7)(8)(9)(10). Similarly, the aberration or absence of WWOX/WWOX expression in primary hematopoietic malignancies has also been reported (11)(12)(13)(14)(15)(16). A recently published study detected the expression of WWOX/WWOX in a small cohort of 38 primary leukemia patients and observed low expression levels (14).…”

“…Our previous studies have demonstrated that WWOX exerts a role as an tumor suppressor gene in leukemia, inhibiting cell proliferation and promoting apoptosis via binding with p73 and triggering of the mitochondrial pathway (14,15). However, the clinical characterization of WWOX in leukemia remains unclear thus far.…”

Beta-Hydroxyisovalerylshikonin Inhibits the Growth of U266 Multiple Myeloma Cells by Triggering the Mitochondrial Pathway

“…The primer sequences for Bcl-2, Bax and GAPDH were previously described [17]. The comparative Ct method was used to calculate the relative expression level of Bcl-2 or Bax as compared with GAPDH.…”