Oncogene Functions of FHL2 Are Independent from NF-κBIα in Gastrointestinal Cancer

Qiao, Liang; Wang, Yan; Pang, Roberta; Wang, Jide; Dai, Yun; Ma, Juan; Gu, Qing; Li, Zesong; Zhang, Yusheng; Zou, Bing; Lan, Hui‐Yao; Wong, Benjamin Chun–Yu

doi:10.1007/s12253-008-9085-1

Cited by 11 publications

(6 citation statements)

References 23 publications

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“…FHL2 has been shown to attenuate NF-κB activity (32) and Ding et al found that FHL2 also inhibited anchoragedependent and -independent growth of hepatocellular carcinoma cells through a TGF-ß-like signaling pathway (15). In contrast to our results Wang et al found that FHL2 inhibition with siRNA induced proliferation and differentiation of the colon cancer cell line Lovo (21) and the same authors described, that suppression of FHL2 decreased NF-κB activity in the colon cancer cell line DLD1 (33). In contrast to HT29 cells, Lovo and DLD1 cells are poorly differentiated colon cancer cell lines and do express high levels of FHL2 (21).…”

Section: Discussioncontrasting

confidence: 92%

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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Section: Discussioncontrasting

confidence: 92%

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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“…Following stimulation with tumor necrosis factor-α, FHL2 downregulation in skeletal muscle cells inhibits the IL-6 secretion [ 8 ]. Additionally, FHL2 promotes activation of nuclear factor (NF)-κB in gastric cancer, liver regeneration, and liver cancer [ 9 , 10 ], and upregulated FHL2 expression in human liver samples is significantly associated with increased inflammatory response and liver cirrhosis [ 11 ]. Moreover, FHL1–3 participate in the phosphorylation of mothers against decapentaplegic homolog-2, which activates the inflammatory response through the mitogen-activated protein kinase signaling pathway [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Autophagy Induced FHL2 Upregulation Promotes IL-6 Production by Activating the NF-κB Pathway in Mouse Aortic Endothelial Cells after Exposure to PM2.5

Xia¹,

Fu²,

Wang

et al. 2017

IJMS

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Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with cardiovascular morbidity and mortality, which share the common feature of PM2.5-induced vascular inflammation; however, the underlying mechanisms of how PM2.5 triggers increased inflammatory response in vascular endothelial cells are not well understood. After treating mouse aortic endothelial cells (MAECs) with different concentrations of PM2.5, we assessed interleukin (IL)-6 and four and a half LIM domains 2 (FHL2) expression in cell supernatant by enzyme-linked immunosorbent assay and Western blot, respectively, as well as activation of nuclear factor (NF)-κB and immune-response signaling pathways. Additionally, changes in pathway activation, IL-6 expression, and autophagy were evaluated under PM2.5 exposure, following FHL2 knockdown with small interfering RNA. Our results indicated that PM2.5 exposure induced FHL2 expression and IL-6 secretion, as well as activation of pathways associated with immune response. Additionally, following FHL2 knockdown, the activation of NF-κB-related pathways and IL-6 secretion was inhibited under PM2.5 exposure, although the Akt- and p38-signaling pathways were not affected. Furthermore, PM2.5 exposure induced autophagy, whereas autophagy inhibition eventually inhibited PM2.5-induced FHL2 expression. These findings suggested a novel link between autophagy induced FHL2 upregulation and IL-6 production in MAECs under PM2.5 exposure.

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“…It is expressed in a cell-and tissue-specific manner, and contributes to the regulation of important cell functions, including cell adhesion, cell transcription and signal transduction (32)(33)(34)(35)(36). It has been reported that FHL2 was overexpressed in PC tissue samples and critically involved in cell survival, radio-resistance, proliferation and apoptosis in PC cells (32 downregulates E-cadherin transcriptional activity, thereby inducing colorectal cancer cell EMT and invasion (27,37,38).…”

Section: Introductionmentioning

confidence: 99%

Krüppel-like factor 8 induces epithelial-to-mesenchymal transition and promotes invasion of pancreatic cancer cells through transcriptional activation of four and a half LIM-only protein 2

Zai

Long

et al. 2017

Oncology Letters

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Abstract. Pancreatic cancer (PC) is one of the most aggressive types of cancer with an extremely poor prognosis. Invasive growth and early metastasis is one of the greatest challenges to overcome for the treatment of PC. Numerous previous studies have indicated that the transcription factor Krüppel-like factor 8 (KLF8) and nuclear cofactor four and a half LIM-only protein 2 (FHL2) serve important roles in tumorigenesis and tumor progression; however, their roles in PC remain elusive. The present study revealed that KLF8 and FHL2 expression is aberrantly co-overexpressed in PC tissue samples and associa ted with tumor metastasis. Furthermore, a positive correlation between the expression levels of KLF8 and FHL2 was observed. Subsequently, the present study identified KLF8 as a critical inducer of epithelial-to-mesenchymal transition (EMT) and invasion. Of note, the present study demonstrated that KLF8 overexpression induced a strong increase in FHL2 expression, and subsequent promoter reporter assays determined that KLF8 directly bound and activated the FHL2 gene promoter. Furthermore, FHL2 knockdown in KLF8-overexpressing cells partially reversed the EMT and invasive phenotypes. The present study identified KLF8-induced FHL2 activation as a novel and critical signaling mechanism underlying human PC invasion.

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Oncogene Functions of FHL2 Are Independent from NF-κBIα in Gastrointestinal Cancer

Cited by 11 publications

References 23 publications

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

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

Autophagy Induced FHL2 Upregulation Promotes IL-6 Production by Activating the NF-κB Pathway in Mouse Aortic Endothelial Cells after Exposure to PM2.5

Krüppel-like factor 8 induces epithelial-to-mesenchymal transition and promotes invasion of pancreatic cancer cells through transcriptional activation of four and a half LIM-only protein 2

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