VEGFR-1 (FLT-1), β1 integrin, and hERG K+ channel for a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome

Pillozzi, Serena; Brizzi, Maria Felice; Bernabei, Pietro Antonio; Bartolozzi, Benedetta; Caporale, Roberto; Basile, Venere; Boddi, Vieri; Pegoraro, Luigi; Becchetti, Andrea; Arcangeli, Annarosa

doi:10.1182/blood-2006-02-003772

Cited by 166 publications

(192 citation statements)

References 46 publications

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“…HERG1 expression increased during head and neck squamous cell carcinoma progression and was significantly associated with lymph node metastasis, advanced disease stages, regional tumor recurrence, distant metastasis and reduced disease-specific survival. Similarly, HERG1 has also been found frequently aberrantly expressed in other types of cancer, such as endometrial cancer, 23 leukemia, 24 glioblastoma, 25 gastric cancer, 26 esophageal squamous cell carcinoma 27 and colorectal cancer, 28 where HERG1 expression commonly correlated with tumor aggressiveness, poor prognosis and metastatic disease.…”

Section: Discussionmentioning

confidence: 99%

Role of HERG1 potassium channel in both malignant transformation and disease progression in head and neck carcinomas

et al. 2012

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Evidence indicates that human ether à -go-go-related gene 1 (HERG1) voltage-gated potassium channels could represent new valuable membrane therapeutic targets and diagnostic/prognostic biomarkers in various cancers. This study is the first to investigate the expression pattern of HERG1 potassium channel subunit in both primary tumors and precancerous lesions to establish its clinical and biological role during the development and progression of head and neck squamous cell carcinomas. HERG1 protein expression was evaluated by immunohistochemistry in paraffin-embedded tissue specimens from 133 patients with laryngeal/ hypopharyngeal squamous cell carcinomas and 75 patients with laryngeal dysplasia, and correlated with clinical data. Our findings demonstrate that HERG1 is frequently aberrantly expressed in a high percentage of primary tumors (87%), whereas expression was negligible in both stromal cells and normal-adjacent epithelia. HERG1 expression increased during head and neck squamous cell carcinoma progression and was significantly associated with lymph node metastasis (P ¼ 0.04), advanced disease stages (Po0.001), regional tumor recurrence (P ¼ 0.004), distant metastasis (P ¼ 0.03) and reduced disease-specific survival (P ¼ 0.012, logrank test). HERG1-positive expression was also detected in 31 (41%) of 75 laryngeal dysplasias. Interestingly, HERG1 expression increased with the grade of dysplasia; however, HERG1 expression but not histology correlated significantly with increased laryngeal cancer risk (P ¼ 0.007). In addition, functional studies in head and neck squamous cell carcinoma-derived cell lines further revealed that HERG1 expression promotes anchorage-dependent and -independent cell growth and invasive capability, although independently of its ionconducting function. Our data demonstrate that HERG1 expression is a biologically and clinically relevant feature in head and neck squamous cell carcinoma progression and also during malignant transformation, and a promising candidate as cancer risk marker and therapeutic target for head and neck squamous cell carcinoma prevention and treatment. Keywords: cancer risk; dysplasia; head and neck squamous cell carcinoma; HERG1; immunohistochemistry; metastasis; potassium channelThe incidence of head and neck squamous cell carcinoma has been gradually increasing over the last three decades. It is the sixth leading cancer by incidence worldwide and only 40-50% of patients with head and neck squamous cell carcinoma will survive for 5 years.1 Two-thirds of the diagnosed tumors present with locally advanced or metastatic disease (stages III and IV) and patients survival is determined by the development of loco-regional recurrences, distant metastases and second primary tumors.2 In this context, the Received

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Section: Discussionmentioning

confidence: 99%

Role of HERG1 potassium channel in both malignant transformation and disease progression in head and neck carcinomas

et al. 2012

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“…To determine BM angiogenesis, BM sections were stained with anti-CD34 antibody, and vascular morphometric parameters were calculated as described previously. 15 The persistence of ICER expression during in vivo experiments was checked in stable transfectants in vitro.…”

Section: In Vivo Assaymentioning

confidence: 99%

ICER expression inhibits leukemia phenotype and controls tumor progression

et al. 2008

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The inducible cyclic AMP (cAMP) early repressor (ICER) and cAMP response element-binding protein (CREB) are transcriptional regulators of the cAMP-mediated signaling pathway. CREB has been demonstrated to be upregulated in the majority of childhood leukemias contributing to disease progression, whereas ICER, its endogenous repressor, was found to be downregulated. Our research focus has been the function of restored ICER expression. ICER exogenously expressed in cell lines decreases CREB protein level and induces a lowered clonogenic potential in vitro. It decreases the ability of HL60 to invade the extramedullary sites and to promote bone marrow angiogenesis in nonobese diabetic-severe combined immunodeficient mice, demonstrating its potential effects on tumor progression. ICER represses the majority of 96 target genes upregulated by CREB. It binds CRE promoters and controls gene expression restoring the normal regulation of major cellular pathways. ICER is subjected to degradation through a constitutively active form of the extracellular signal-regulated protein kinase, which drives it to the proteasome. We propose that ICER is downregulated in HL60 to preserve CREB overexpression, which disrupts normal myelopoiesis and promotes blast proliferation. These findings define the function of ICER as a tumor suppressor in leukemia. Unbalanced CREB/ICER expression needs to be considered a pathogenetic feature in leukemogenesis. The molecular characterization of this pathway could be useful for novel therapeutic strategies.

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“…APC Min/ þ animals show overexpression of several members of the Eag family of Kv channels, as well as of BK channels. Erg channels are activated by Akt (Zhang et al, 2003) and confer greater malignancy to patients with leukemia (Pillozzi et al, 2007). Moreover, mutations in the APC gene alter cell cycling (Dikovskaya et al, 2007), and as Eag family channels are cell cycle regulated (Wonderlin and Strobl, 1996), it is likely that these changes affect their activity.…”

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confidence: 99%

Rapamycin inhibits oncogenic intestinal ion channels and neoplasia in APCMin/+ mice

et al. 2009

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The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis. Mice with a heterozygous APC Min mutation develop multiple intestinal neoplasia (Min) leading to premature death. Early in colorectal carcinogenesis, APC Min/ þ mice show enhanced Akt-mammalian target of rapamycin (mTOR) signaling, which is paralleled by upregulation of oncogenic K þ channels. In this study, we tested the effect of mTOR inhibition with rapamycin on tumor formation in APC Min/ þ mice and evaluated ion channel regulation. We found that continuous long-term rapamycin treatment of APC Min/ þ mice dramatically inhibits intestinal neoplasia. Moreover, although untreated APC Min/ þ mice lose weight, experience intestinal bleeding and succumb to multiple neoplasia by 22.3±1.4 weeks of age, mice treated with rapamycin maintain stable weight and survive long term (39.6 ± 3.4 weeks), with more than 30% surviving >1 year. Impressively, abnormalities in colonic electrolyte transport typical for APC Min/ þ mice are abolished, along with the suppression of epithelial Na þ channel (ENaC) and oncogenic K þ ion channels BK, Elk1 and Erg1, both functionally and at mRNA levels. These results show that continuous prophylaxis by rapamycin markedly inhibits the development of APC mutation-related polyposis, and suggest a novel contributing mechanism of action through the blockade of intestinal oncogenic ion channels.

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VEGFR-1 (FLT-1), β1 integrin, and hERG K+ channel for a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome

Cited by 166 publications

References 46 publications

Role of HERG1 potassium channel in both malignant transformation and disease progression in head and neck carcinomas

Role of HERG1 potassium channel in both malignant transformation and disease progression in head and neck carcinomas

ICER expression inhibits leukemia phenotype and controls tumor progression

Rapamycin inhibits oncogenic intestinal ion channels and neoplasia in APCMin/+ mice

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