Higher bone marrow LGALS3 expression is an independent unfavorable prognostic factor for overall survival in patients with acute myeloid leukemia

Cheng, Chieh Lung; Hou, Hsin An; Lee, Ming Cheng; Liu, Chieh‐Yu; Jhuang, Jie Yang; Lai, Yan Jun; Lin, Chung-Wu; Chen, Huan Yuan; Liu, Fu Tong; Chou, Wen‐Chien; Chen, Chien Yuan; Tang, Jih-Luh; Yao, Ming; Huang, Shang Yi; Ko, Bor-Sheng; Wu, Shipher; Tsay, Woei; Tien, Hwei‐Fang

doi:10.1182/blood-2012-07-443762

Cited by 51 publications

(35 citation statements)

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“…In the multivariate analysis, we observed that galectin-3 expression, together with some traditional prognostic factors (tumor size, histologic grade) were independent risk factors in the prognosis of HCC patients. Similar findings have been reported in other malignancies [26-29]. …”

Section: Discussionsupporting

confidence: 91%

Galectin-3 is associated with a poor prognosis in primary hepatocellular carcinoma

et al. 2014

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BackgroundGalectin-3, a member of the beta-galactoside-binding lectin family, is a multifunctional protein with various biological functions, including the proliferation and differentiation of tumor cells, angiogenesis, cancer progression, and metastasis. We aimed to clarify if expression of galectin-3 is related to the clinicopathological characteristics and prognosis of hepatocellular carcinoma (HCC) patients, and to explore the possible mechanisms of galectin-3 in hepatocellular carcinoma.MethodsFirst, we investigated galectin-3 mRNA and protein expression by using RT-PCR and Western blotting. Second, tissues from 165 HCC patients were used to evaluate clinicopathological characteristics and prognosis through immunohistochemical analyses. Furthermore, the functions of galectin-3 were analyzed with respect to the proliferation, cell cycle,apoptosis, migration, and invasion of HCC cell lines. Finally, we analyzed galectin-3 expression and micro-vessel density (MVD) by immunohistochemistry (IHC) to find its correlation with angiogenesis in Hepatocellular Carcinoma. Flow cytometer was used to explore apoptosis and Western-blot was used to detect the pathway proteins of apoptosis.ResultsGalectin-3 showed high expression at the mRNA and protein levels in HCC cancer tissues and cell lines. Clinicopathological analyses revealed that increased expression of galectin-3 in tumors was closely associated with a poor prognosis. Galectin-3 knockdown by siRNA significantly inhibited cell growth, migration, and invasion, and induced apoptosis in HCC cells in vitro, whereas galectin-3 overexpression promoted cell growth, migration, and invasion. Correlation analysis of galectin-3 expression and micro-vessel density (MVD) showed that galectin-3 expression in tumor cells stimulates angiogenesis. The observed regulation of cell apoptosis was accompanied by the galectin-3-mediated modulation of caspase3 signaling pathways in HCC cells.ConclusionsThese data suggest that galectin-3 plays an important part in HCC progression and may serve as a prognostic factor for HCC.

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Section: Discussionsupporting

confidence: 91%

Galectin-3 is associated with a poor prognosis in primary hepatocellular carcinoma

et al. 2014

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“…have been shown to be prognostic for poor survival in many cancers including leukemia, lymphomas, breast cancer, and thyroid cancer but decreased levels of Galectin 3 appear to be detrimental to patients with chronic lymphoblastic leukemia (CLL) or prostate cancer (23,36,(54)(55)(56)(57). A possible explanation for this variance could involve the intra-cellular localization of Galectin 3 within the cancer cells as the molecule's function will vary depending on whether it is in the nucleus, cytoplasm, nucleus, or extracellular spaces for that matter (23).…”

Section: ) the Role Of Galectin 3 In Various Cancers Is Complex Asmentioning

confidence: 99%

Galectin 3 as a guardian of the tumor microenvironment

Ruvolo

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

175

165

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Galectin 3 is a member of a family of β-galactoside binding proteins and has emerged as an important regulator of diverse functions critical in cancer biology including apoptosis, metastasis, immune surveillance, molecular trafficking, mRNA splicing, gene expression, and inflammation. Galectin 3's ability to support cancer cell survival by intra-cellular and extra-cellular mechanisms suggests this molecule is an important component of the tumor microenvironment that potentially could be targeted for therapy. Data is emerging that Galectin 3 is elevated in many cancers including solid tumors and the cancers of the blood. Galectin 3 also appears to be a key molecule produced by tumor microenvironment support cells including mesenchymal stromal cells (MSC) to suppress immune surveillance by killing T cells and interfering with NK cell function and by supporting metastasis. Levels of Galectin 3 increase in the MSC of aging mice and perhaps this contributes to the development of cancer in the elderly. Galectin 3 modulates surface protein expression of a diverse set of glycoproteins including CD44 by regulating endocytosis of these proteins. In addition, Galectin 3 binding to receptor kinases such as CD45 and the T cell receptor is critical in the regulation of their function. In this review I will examine the various mechanisms how Galectin 3 supports chemoresistance and metastasis in solid tumors and in leukemia and lymphoma. I will also discuss possible therapeutic strategies to target this Galectin for cancer therapy. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

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“…LGALS3 has clinical relevance as a target in many cancers [20, 30, 31]. Cheng and colleagues reported that elevated LGALS3 was prognostic for poor survival in AML patients [31].…”

Section: Introductionmentioning

confidence: 99%

Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells

Ruvolo

Benton

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Galectin 3 (LGALS3) expression is prognostic for poor survival in acute myeloid leukemia (AML) patients. GCS-100 is a novel galectin inhibitor that may prove useful for AML therapy. In this study, we found GCS-100 induced apoptosis in AML cells. The agent reduced MCL-1 expression suggesting GCS-100 could be more effective when combined with a BH3 mimetic. Indeed, potent synergistic cytotoxicity was achieved when GCS-100 was combined with ABT-737 or ABT-199. Furthermore, the GCS-100/ABT-199 combination was effective against primary AML blast cells from patients with FLT3 ITD mutations, which is another prognostic factor for poor outcome in AML. This activity may involve wild-type p53 as shRNA knockdown of LGALS3 or galectin 1 (LGALS1) sensitized wild-type p53 OCI-AML3 cells to GCS-100/ABT-737-induced apoptosis to a much greater extent than p53 null THP-1 cells. Suppression of LGALS3 by shRNA inhibited MCL-1 expression in OCI-AML3 cells, but not THP-1 cells, suggesting the induced sensitivity to ABT-737 may involve a MCL-1 mediated mechanism. OCI-AML3 cells with LGALS1 shRNA were also sensitized to ABT-737. However, these cells exhibited increased MCL-1 expression, so MCL-1 reduction is apparently not required in this process. A role for p53 appears important as GCS-100 induces p53 expression and shRNA knockdown of p53 protected OCI-AML3 cells from the cytotoxic effects of the GCS-100/ABT-737 treatment combination. Our results suggest that galectins regulate a survival axis in AML cells, which may be targeted via combined inhibition with drugs such as GCS-100 and ABT-199.

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Higher bone marrow LGALS3 expression is an independent unfavorable prognostic factor for overall survival in patients with acute myeloid leukemia

Abstract: Key Points Bone marrow LGALS3 expression is associated with distinct clinical and biological features in patients with acute myeloid leukemia. Higher bone marrow LGALS3 expression is an independent poor prognostic factor for overall survival and may serve as a potential therapeutic target.

Cited by 51 publications

References 48 publications

Galectin-3 is associated with a poor prognosis in primary hepatocellular carcinoma

Galectin-3 is associated with a poor prognosis in primary hepatocellular carcinoma

Galectin 3 as a guardian of the tumor microenvironment

Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells

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