Latexin exhibits tumor suppressor potential in hepatocellular carcinoma

Ni, Qingfeng; Tian, Yuan; Kong, Liangliang; Lu, Yeting; Ding, Wenzhou; Kong, Lianbao

doi:10.3892/or.2014.2966

Cited by 17 publications

(17 citation statements)

References 33 publications

(31 reference statements)

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“…We and others have shown that Lxn is downregulated in leukemia, lymphoma, and several other cancers (Li et al., 2011, Liu et al., 2012, Mitsunaga et al., 2012, Abd Elmageed et al., 2013, Muthusamy et al., 2013, Ni et al., 2014). Since young Lxn −/− mice did not show any obvious sign of hematological malignancy, we asked whether aging could promote tumor development in Lxn −/− mice.…”

Section: Resultsmentioning

confidence: 99%

Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice

Liu

Zhang

et al. 2017

Stem Cell Reports

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SummaryNatural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1) was a potential downstream target with a dramatic downregulation in Lxn-null HSCs. Enforced expression of Thbs1 restored the Lxn inactivation-mediated HSC phenotypes. This study reveals that Lxn plays an important role in the maintenance of homeostatic hematopoiesis, and it may lead to development of safe and effective approaches to manipulate HSCs for clinical benefit.

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Section: Resultsmentioning

confidence: 99%

Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice

Liu

Zhang

et al. 2017

Stem Cell Reports

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“… 3 It is downregulated in several types of solid and liquid tumors, and overexpression of Lxn inhibits tumor cell growth. 4 , 5 , 6 , 7 , 8 In lymphoma, the tumor suppressor function of Lxn is mediated through Bcl-2-induced apoptosis. 5 Moreover, Lxn was reported to be a TNF-responsive gene in human papillovirus-infected keratinocytes, suggesting that it may contribute to TNF-induced suppression of cervical cancer.…”

mentioning

confidence: 99%

Latexin sensitizes leukemogenic cells to gamma-irradiation-induced cell-cycle arrest and cell death through Rps3 pathway

et al. 2014

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Leukemia is a leading cause of cancer death. Recently, the latexin (Lxn) gene was identified as a potential tumor suppressor in several types of solid tumors and lymphoma, and Lxn expression was found to be absent or downregulated in leukemic cells. Whether Lxn functions as a tumor suppressor in leukemia and what molecular and cellular mechanisms are involved are unknown. In this study, the myeloid leukemogenic FDC-P1 cell line was used as a model system and Lxn was ectopically expressed in these cells. Using the protein pull-down assay and mass spectrometry, ribosomal protein subunit 3 (Rps3) was identified as a novel Lxn binding protein. Ectopic expression of Lxn inhibited FDC-P1 growth in vitro. More surprisingly, Lxn enhanced gamma irradiation-induced DNA damages and induced cell-cycle arrest and massive necrosis, leading to depletion of FDC-P1 cells. Mechanistically, Lxn inhibited the nuclear translocation of Rps3 upon radiation, resulting in abnormal mitotic spindle formation and chromosome instability. Rps3 knockdown increased the radiation sensitivity of FDC-P1, confirming that the mechanism of action of Lxn is mediated by Rps3 pathway. Moreover, Lxn enhanced the cytotoxicity of chemotherapeutic agent, VP-16, on FDC-P1 cells. Our study suggests that Lxn itself not only suppresses leukemic cell growth but also potentiates the cytotoxic effect of radio- and chemotherapy on cancer cells. Lxn could be a novel molecular target that improves the efficacy of anti-cancer therapy.

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“…LXN has homology to two other proteins/genes, tazarotene-induced gene 1 (TIG1) and cystatin C, both of which have been reported to be tumor suppressors (36,37). LXN expression has been suggested to be a tumor suppressor itself as it has been shown to inhibit tumor cell growth in gastric cancer (14), leukemia (15), melanoma (16), PCa (38), hepatocellular carcinoma (39) and breast cancer (40). In addition to being a potential tumor suppressor, LXN negatively regulates hematopoietic stem cell self-renewal in mice, resulting in an inverse relationship between LXN expression and HSC population size (17,18,41).…”

Section: Discussionmentioning

confidence: 99%

Bone Microenvironment Changes in Latexin Expression Promote Chemoresistance

Zhang

Osisami

Dai

et al. 2017

Molecular Cancer Research

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Although docetaxel (DOX) is the standard of care for advanced prostate cancer (PCa), most patients develop resistance to DOX. Therefore, elucidating the mechanism that underlies resistance to DOX is critical to enhance therapeutic intervention. Mining cDNA microarray from the PC-3 PCa cell line and its DOX-resistant derivative (PC3-TxR) revealed decreased latexin (LXN) expression in the resistant cells. LXN expression was inversely correlated with taxane resistance in a panel of PCa cell lines. LXN knockdown conferred DOX resistance to PCa cells in vitro and in vivo; whereas LXN overexpression reduced DOX resistance in several PCa cell lines. A mouse model of PCa demonstrated that PCa cells developed resistance to DOX in the bone microenvironment, but not the soft tissue microenvironment. This was associated with decreased LXN expression in PCa cells in the bone microenvironment compared to the soft tissue microenvironment. It was identified that bone stromal cells decreased LXN expression through methylation and induced chemoresistance in PCa in vitro. These findings reveal that a subset of PCa develops DOX resistance through loss of LXN expression associated with methylation and that the bone microenvironment promotes this drug resistance phenotype.

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Latexin exhibits tumor suppressor potential in hepatocellular carcinoma

Cited by 17 publications

References 33 publications

Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice

Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice

Latexin sensitizes leukemogenic cells to gamma-irradiation-induced cell-cycle arrest and cell death through Rps3 pathway

Bone Microenvironment Changes in Latexin Expression Promote Chemoresistance

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