The four‐and‐a‐half‐LIM protein 2 (FHL2) is overexpressed in gliomas and associated with oncogenic activities

Li, Ming; Wang, Jide; Ng, Sophia; Chan, Cerise Yuen‐Ki; Chen, Amy C.; Xia, Hong Ping; Yew, David T.; Wong, Benjamin Chun–Yu; Chen, Zhu; Kung, Hsiang‐Fu; Lin, Marie Chia‐mi

doi:10.1002/glia.20701

Cited by 29 publications

(27 citation statements)

References 34 publications

(39 reference statements)

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“…An altered FHL2 expression was observed in osteosarcoma cells treated with plumbagin, similarly to the results reported in previous studies (35,39). In addition, previous studies have demonstrated that FHL2 gene expression in human soft tissue cancers is variable depending on the cell type; FHL2 was revealed to be overexpressed in breast cancer (40), glioma (41), lung cancer (42), colon carcinoma (20) and gastrointestinal cancer (43) cells compared with cells from normal tissue.…”

Section: Discussionsupporting

confidence: 88%

Plumbagin exhibits an anti-proliferative effect in human osteosarcoma cells by downregulating FHL2 and interfering with Wnt/β-catenin signalling

Xue

Meng

et al. 2016

Oncology Letters

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Abstract. Plumbagin, a naphthoquinone constituent of Plumbago zeylanica L. (Plumbaginaceae) is widely used in traditional Chinese medicine as an antifungal, antibacterial and anti-inflammatory agent. Plumbagin is known to exhibit proapoptotic, antiangiogenic and antimetastatic effects in cancer cells. The transcriptional co-factor four and a half LIM domains 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of gene expression, signal transduction and cell proliferation and differentiation, and also acts as a tumor suppressor or oncoprotein depending on the tissue microenvironment. The present study investigated the effect of plumbagin on FHL2 expression, Wnt/β-catenin signalling and its anti-proliferative activity in various human osteosarcoma cell lines, including SaOS2, MG63, HOS and U2OS. The cells were exposed to plumbagin and the expression of FHL2 was evaluated using western blot analysis. Furthermore, the anti-proliferative effect of plumbagin was evaluated using a 3-(4,5 dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In addition, since FHL2 is involved in Wnt/β-catenin signaling, the effect of plumbagin on β-catenin and its primary target genes, including v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) and WNT1 inducible signaling pathway protein-1 (WISP-1), was evaluated using western blot analysis. It was observed that plumbagin suppressed the expression of FHL2 and exhibited significant anti-proliferative activity in osteosarcoma cells. It also attenuated Wnt/β-catenin signalling by downregulating β-catenin and its target genes, including c-Myc and WISP-1. In conclusion, plumbagin demonstrated anti-proliferative activity in osteosarcoma cells by downregulating FHL2 and interfering with Wnt/β-catenin signalling.

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Section: Discussionsupporting

confidence: 88%

Plumbagin exhibits an anti-proliferative effect in human osteosarcoma cells by downregulating FHL2 and interfering with Wnt/β-catenin signalling

Xue

Meng

et al. 2016

Oncology Letters

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“…Moreover, these A549 Ú -cells, whilst able to grow in mouse xenografts, required longer induction periods with smaller tumours than their Ú + parents. This suggests a clear difference in phenotype, perhaps due to differences in nuclear gene expression (96)(97)(98). Similar results have been noted in breast cancer cells (99).…”

Section: Creation Of Mtdna-less Cells (ú -) Cavalli Et Alsupporting

confidence: 80%

The importance of mitochondria in the tumourigenic phenotype: Gliomas as the paradigm (Review)

Liang¹

2011

Int J Mol Med

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Abstract. Cancer arises from the accumulation of nuclear and cytoplasmic abnormalities, a phenomenon allowing for the expression of the tumourigenic phenotype. Gliomas represent the most frequently diagnosed tumours of the central nervous system in adults. Warburg hypothesized the importance of glycolysis in cancer cells, and implicated additional roles of mitochondria in neoplasia. Recent data have shown the importance of mitochondria in the tumourigenic phenotype, in particular, within the apoptotic process. There have been a variety of studies conducted on brain tumours revealing significant alterations of mitochondria within the tumourigenic phenotype. This review describes some of the more recent findings of mitochondria and gliomas, correlating findings to those observed in other cancers. Alterations in mitochondrial DNA copy number and location, as well as dependence of the cancer cell phenotype on mitochondria are emphasised. In addition to its role in apoptosis, the mitochondrion serves as an important element in the tumourigenic phenotype, and clinical approaches targeting this organelle have potential for the development of effective treatment regimens for patients with glioma and other neoplastic diseases.

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“…Previous studies have shown that FHL2 may act as both an oncoprotein or a tumor suppressor depending on the type of cancer (13)(14)(15)(16)(17)(18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

“…FHL2 was first identified in human rhabdomyosarcoma cells as a downregulated gene indicating a role as tumor suppressor (13) and reduced FHL2 expression was also found in prostate and hepatocellular cancer (14,15). In contrast, increased expression of FHL2 was detected in breast, lung, and ovarian cancer, as well as glioblastoma and melanoma (16)(17)(18)(19)(20). Further, Wang et al found higher FHL2 expression in colon cancerous tissues compared to normal tissues, and the same authors described, that suppression of FHL2 in a colon cancer cell line with endogenously high FHL2 expression inhibited tumor growth (21).…”

Section: Introductionmentioning

confidence: 99%

FHL2 suppresses growth and differentiation of the colon cancer cell line HT-29

Amann

Egle²,

Boßerhoff³

et al. 2010

Oncol Rep

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Abstract. Four and a half LIM domain protein 2 (FHL2) can interact with many proteins and regulates different cellular processes, including proliferation and differentiation. FHL2 expression is often deregulated in cancer and may act as both tumor-promoter or tumor-suppressor depending on the type of cancer. Thus, a previous study found that increased FHL2 expression in colon cancer and suppression of FHL2 in a colon cancer cell line with endogenously high FHL2 expression inhibited tumor growth. We applied the opposite strategy, an FHL2 expression plasmid was stably transfected into HT-29 cells, a colon carcinoma cell line which exhibits very low basal levels of FHL2. Stable expression of FHL2 in HT-29 cells induced a G2/M arrest and inhibited anchorage-dependent and -independent growth in vitro. Further, FHL2 expressing HT-29 cell clones revealed significantly higher expression of the differentiation marker E-cadherin but reduced activity of the transcription factor NF-κB, which is known to promote colon cancer progression. These findings further underscore the complex role of FHL2 in tumorigenicity, with even different effects on cellular functions of cancer cell lines derived from the same type of tumor and distinctly suggest caution regarding therapeutic strategies targeting FHL2 to treat (colon) cancer. IntroductionColorectal cancer (CRC) is one of the most frequent human tumors and the third leading cause of cancer death (1). The prognosis of CRC, especially advanced cancer, has not substantially improved although the molecular mechanisms of CRC have become better understood in the past two decades (2).Four and a half LIM protein 2 (FHL2), also known as down-regulated in rhabdomyosarcoma LIM (DRAL) domain protein, is a member of a small family of five proteins with four and a half LIM domains (3). The abbreviation LIM represents the names of three transcription factors (Lin-11, Isl-1 and Mec-3) in which such a domain was first identified (4). The LIM domains are double zinc finger motifs that play multiple roles in protein-protein interaction (5). FHL2 can interact with >50 different proteins with diverse functions such as receptors, enzymes, transcription factors, cofactors or splicing factors (6). Thus, FHL2 is involved in the regulation of various cellular processes including proliferation, differentiation, migration and contraction (7-10). FHL2 can function as repressor or activator of transcriptional activity, and noteworthy, depending on the cell type even the expression of the same gene or distinguished cellular functions, respectively, may be regulated in different ways. Thus, FHL2 promotes expression of ·-smooth-muscle actin (·-SMA) and contractility in myofibroblasts of the skin (9), but inhibits ·-SMA expression and contractility of cardiac muscle cells (11).Also the role of FHL2 in tumorigenesis is complex, since it may act as an oncoprotein or as a tumor suppressor depending on the type of cancer (6,12). FHL2 was first identified in human rhabdomyosarcoma cells as a downregulated gene indicati...

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The four‐and‐a‐half‐LIM protein 2 (FHL2) is overexpressed in gliomas and associated with oncogenic activities

Cited by 29 publications

References 34 publications

Plumbagin exhibits an anti-proliferative effect in human osteosarcoma cells by downregulating FHL2 and interfering with Wnt/β-catenin signalling

Plumbagin exhibits an anti-proliferative effect in human osteosarcoma cells by downregulating FHL2 and interfering with Wnt/β-catenin signalling

The importance of mitochondria in the tumourigenic phenotype: Gliomas as the paradigm (Review)

FHL2 suppresses growth and differentiation of the colon cancer cell line HT-29

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