Gene Summary

Gene:AMFR; autocrine motility factor receptor
Aliases: GP78, RNF45
Summary:This locus encodes a glycosylated transmembrane receptor. Its ligand, autocrine motility factor, is a tumor motility-stimulating protein secreted by tumor cells. The encoded receptor is also a member of the E3 ubiquitin ligase family of proteins. It catalyzes ubiquitination and endoplasmic reticulum-associated degradation of specific proteins. [provided by RefSeq, Feb 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:E3 ubiquitin-protein ligase AMFR
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AMFR (cancer-related)

Li Y, Jia Y, Bian Y, et al.
Autocrine motility factor promotes endometrial cancer progression by targeting GPER-1.
Cell Commun Signal. 2019; 17(1):22 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Autocrine motility factor (AMF) is a critical factor regulating aggressiveness of endometrial cancer (EC). Multiple pieces of evidence indicate that it is through G protein coupled estrogen receptor (GPER) signaling pathway that some growth factors promoted the migration and proliferation of tumor cells. The aim of this study is to explore the role of GPER-1 in AMF mediated regulatory mechanisms of EC recurrence and progression.
METHODS: Real-Time Cell Analysis (RTCA) assays were performed to assess whether AMF depends on Autocrine motility factor recepter (AMFR) signaling in EC cells. A genome-wide expression microarray and Yeast Two-Hybrid assay were used to detect AMF and GPER-1 interaction in the context of AMFR depletion, and co-immunoprecipitation and immunofluorescence experiments were performed to confirm the physical interaction. Isobaric Tags for Relative and Absolute Quantification (iTRAQ) analysis was used for the identification of the target pathway activated by AMF-GPER-1 interaction. Cohorts of mice harboring xenografts derived from modified SPEC2 cell lines were treated with or without exogenous AMF to validate the results of previous experiments. Immunohistochemistry was performed to assess AMF and GPER-1 expression in endometrial cancer specimens and normal endometrium.
RESULTS: Our data showed that GPER-1 binds to AMF and the formed complex translocates from the plasma membrane to the cytoplasm. Mechanistic investigations demonstrated that interaction between AMF and GPER-1 triggers phosphoinositide-3-kinase signaling and promotes EC cell growth. More importantly, through animal experiments and human tissue experiments, we found that AMF contributes to GPER-1-mediated EC progression, which is consistent with the above observations.
CONCLUSIONS: Our work not only delineated the regulatory mechanisms of endometrial cancer progression by AMF-GPER-1-AKT signaling cascade but also laid the foundation of targeting this pathway for treating endometrial cancer.

Duan F, Jiang J, Song C, et al.
Functional long non-coding RNAs associated with gastric cancer susceptibility and evaluation of the epidemiological efficacy in a central Chinese population.
Gene. 2018; 646:227-233 [PubMed] Related Publications
AIM: To screen and validate the gastric cancer-associated long non-coding RNAs (lncRNAs) and their functional single nucleotide polymorphisms (SNPs).
METHODS: Based on case-control design, we select the differentially expressed lncRNAs by bioinformation tools and validate SNPs in lncRNAs genes in population. Attributable risk percentage (ARP) and population attributable risk percentage (PARP) were used to assess the effect of epidemiology.
RESULTS: Four lncRNAs with SNPs (lnc-EVX1-3:3 (rs1859168), lnc-MACC1-1:7 (rs3815254), lnc-AMFR-1:1 (rs4784659) and lnc-ZNF33B-2:1 (rs579501)) were selected to be validated in population. The unconditional multiple logistic regression based on the dominant (odds ratio, OR=0.64, 95%confidence interval, 95%CI: 0.47-0.86) and recessive genetic model (OR=1.77, 95%CI: 1.34-2.35) showed rs1859168 was significantly associated with lower risk of gastric cancer. The dominant (OR=0.42, 95%CI:0.31-0.57) and additive (OR=0.52, 95%CI:0.40-0.67) genetic model revealed that rs4784659 decreased the risk of gastric cancer. Similarly, the dominant (OR=0.72, 95%CI: 0.52-0.98) and additive (OR=0.73, 95%CI: 0.56-0.97) genetic model showed the individuals with rs579501 had reduced risk of gastric cancer. Whereas no statistical association between rs3815254 and gastric cancer. ARP and PARP for gastric cancer associated with rs1859168 in dominant model (56.25%, 33.05%), and in recessive model (43.50% and 29.37%). For rs4784659, ARP and PARP were 138.09% and 10.39% in dominant model, 92.31% and 8.76% in additive model. For rs579501, ARP and PARP were 38.89% and 4.03% in dominant model, 36.99% and 3.88% in additive model.
CONCLUSION: Our findings showed rs4784659, rs579501 and rs1859168 reduced the susceptibility of gastric cancer. From epidemiological perspective, the lncRNAs with SNPs attenuate the development of gastric cancer.

Lee JH, Han YS, Yoon YM, et al.
Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis.
Oncogene. 2017; 36(47):6555-6567 [PubMed] Related Publications
The cellular prion protein (PrP

Li J, Alyamani M, Zhang A, et al.
Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer.
Elife. 2017; 6 [PubMed] Free Access to Full Article Related Publications
Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.

Erzurumlu Y, Ballar P
Androgen Mediated Regulation of Endoplasmic Reticulum-Associated Degradation and its Effects on Prostate Cancer.
Sci Rep. 2017; 7:40719 [PubMed] Free Access to Full Article Related Publications
The endoplasmic reticulum (ER) comprises thirty percent of the newly translated proteins in eukaryotic cells. The quality control mechanism within the ER distinguishes between properly and improperly folded proteins and ensures that unwanted proteins are retained in the ER and subsequently degraded through ER-associated degradation (ERAD). Besides cleaning of misfolded proteins ERAD is also important for physiological processes by regulating the abundance of normal proteins of the ER. Thus it is important to unreveal the regulation patterns of ERAD. Here, we describe that ERAD pathway is regulated by androgen, where its inhibitor SVIP was downregulated, all other ERAD genes were upregulated. Consistently, androgen treatment increased the degradation rate of ERAD substrates. Using several independent techniques, we showed that this regulation is through androgen receptor transactivation. ERAD genes found to be upregulated in prostate cancer tissues and silencing expression of Hrd1, SVIP, and gp78 reduced the in vitro migration and malignant transformation of LNCaP cells. Our data suggests that expression levels of ERAD components are regulated by androgens, that promotes ERAD proteolytic activity, which is positively related with prostate tumorigenesis.

Lucarelli G, Rutigliano M, Sanguedolce F, et al.
Increased Expression of the Autocrine Motility Factor is Associated With Poor Prognosis in Patients With Clear Cell-Renal Cell Carcinoma.
Medicine (Baltimore). 2015; 94(46):e2117 [PubMed] Free Access to Full Article Related Publications
Glucose-6-phosphate isomerase (GPI), also known as phosphoglucose isomerase, was initially identified as the second glycolytic enzyme that catalyzes the interconversion of glucose-6-phosphate to fructose-6-phosphate. Later studies demonstrated that GPI was the same as the autocrine motility factor (AMF), and that it mediates its biological effects through the interaction with its surface receptor (AMFR/gp78). In this study, we assessed the role of GPI/AMF as a prognostic factor for clear cell renal cell carcinoma (ccRCC) cancer-specific (CSS) and progression-free survival (PFS). In addition, we evaluated the expression and localization of GPI/AMF and AMFR, using tissue microarray-based immunohistochemistry (TMA-IHC), indirect immunofluorescence (IF), and confocal microscopy analysis.Primary renal tumor and nonneoplastic tissues were collected from 180 patients who underwent nephrectomy for ccRCC. TMA-IHC and IF staining showed an increased signal for both GPI and AMFR in cancer cells, and their colocalization on plasma membrane. Kaplan-Meier curves showed significant differences in CSS and PFS among groups of patients with high versus low GPI expression. In particular, patients with high tissue levels of GPI had a 5-year survival rate of 58.8%, as compared to 92.1% for subjects with low levels (P < 0.0001). Similar findings were observed for PFS (56.8% vs 93.3% at 5 years). At multivariate analysis, GPI was an independent adverse prognostic factor for CSS (HR = 1.26; P = 0.001), and PFS (HR = 1.16; P = 0.01).In conclusion, our data suggest that GPI could serve as a marker of ccRCC aggressiveness and a prognostic factor for CSS and PFS.

Li Y, Che Q, Bian Y, et al.
Autocrine motility factor promotes epithelial-mesenchymal transition in endometrial cancer via MAPK signaling pathway.
Int J Oncol. 2015; 47(3):1017-24 [PubMed] Related Publications
Autocrine motility factor (AMF) as a cytokine and a growth factor, is known to regulate tumor cell growth and motility in the progress of various human malignant tumors, however, its role in endometrial cancer (EC) has not been fully studied. In the present study, using immunohistochemistry, we found that AMF was highly expressed in EC tissues compared with normal endometrial tissues and tissue micrioarray technology showed positive correlation between AMF expression and epithelial-to-mesenchymal transition (EMT) related markers E-cadherin, vimentin and Snail. Next, we detected that silencing of AMF by stable transfection with shRNA induced mesenchymal-to-epithelial transition phenotype in Ishikawa and HEC-1B cells by qRT-PCR, western blotting and immunofluorescence. Gene expression profile revealed that AMF silencing resulted in altered expression of EMT related molecular mediators including Snail and transforming growth factor β receptor 1, and involvement of mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, we found that EMT related markers were downregulated with pretreatment of the MAPK-specific inhibitor U0126 by western blotting. The present study is the first to support a role for AMF mediating EMT in endometrial cancer through MAPK signaling. Therefore, AMF may provide a potential prognostic and therapeutic target in preventing EC progression.

Wang Y, Ma L, Wang C, et al.
Autocrine motility factor receptor promotes the proliferation of human acute monocytic leukemia THP-1 cells.
Int J Mol Med. 2015; 36(3):627-32 [PubMed] Free Access to Full Article Related Publications
The aberrant activation of autocrine motility factor receptor (AMFR) has been implicated in several types of human cancer. The present study aimed to elucidate the effect of AMFR on the regulation of proliferation in an acute monocytic leukemia cell line, THP‑1. THP‑1 cells were transfected with AMFR‑targeted small interfering (si)RNA and a plasmid encoding a truncated AMFR, AMFR‑C, (pcDNA3.1‑AMFR‑C). The mRNA and protein levels of AMFR and the downstream targets, rho‑associated, coiled‑coil containing protein kinase 2 (ROCK2), cyclin D1, and B‑cell lymphoma (Bcl)‑2, were measured using reverse transcription‑quantitatibe polymerase chain reaction and immunoblot analyses. The effects on cell cycle and apoptosis were investigated using flow cytometry. The present study successfully established the knockdown of AMFR and expression of AMFR‑C in the THP‑1 cells. Downregulation of AMFR induced cell cycle arrest at the G0/G1 phase, and increased apoptosis of the THP‑1 cells (all P<0.05). The AMFR siRNA increased the percentage of early apoptotic cells between 3.88±1.43 and 19.58±4.29% (P<0.05). The expression levels of ROCK2, cyclin D1 and Bcl‑2 were reduced by the downregulation of AMFR and enhanced by overexpression of AMFR‑C. In conclusion, AMFR appears to be crucial for the proliferation of the THP‑1 acute monocytic leukemia cell line. Therefore, AMFR may represent a potential target for the treatment of acute monocytic leukemia.

Chang YW, Tseng CF, Wang MY, et al.
Deacetylation of HSPA5 by HDAC6 leads to GP78-mediated HSPA5 ubiquitination at K447 and suppresses metastasis of breast cancer.
Oncogene. 2016; 35(12):1517-28 [PubMed] Related Publications
Heat-shock protein 5 (HSPA5) is a marker for poor prognosis in breast cancer patients and has an important role in cancer progression, including promoting drug resistance and metastasis. In this study, we identify that the specific lysine residue 447 (K447) of HSPA5 could be modified with polyubiquitin for subsequent degradation through the ubiquitin proteasomal system, leading to the suppression of cell migration and invasion of breast cancer. We further found that GP78, an E3 ubiquitin ligase, interacted with the C-terminal region of HSPA5 and mediated HSPA5 ubiquitination and degradation. Knock down of GP78 significantly increased the expression of HSPA5 and enhanced migration/invasive ability of breast cancer cells. Knock down of histone deacetylase-6 (HDAC6) increased the acetylation of HSPA5 at lysine residues 353 (K353) and reduced GP78-mediated ubiquitination of HSPA5 at K447 and then increased cell migration/invasion. In addition, we demonstrate that E3 ubiquitin ligase GP78 preferentially binds to deacetylated HSPA5. Notably, the expression levels of GP78 inversely correlated with HSPA5 levels in breast cancer patients. Patients with low GP78 expression significantly correlated with invasiveness of breast cancer, advanced tumor stages and poor clinical outcome. Taken together, our results provide new mechanistic insights into the understanding that deacetylation of HSPA5 by HDAC6 facilitates GP78-mediated HSPA5 ubiquitination and suggest that post-translational regulation of HSPA5 protein is critical for HSPA5-mediated metastatic properties of breast cancer.

Chang YW, Chen HA, Tseng CF, et al.
De-acetylation and degradation of HSPA5 is critical for E1A metastasis suppression in breast cancer cells.
Oncotarget. 2014; 5(21):10558-70 [PubMed] Free Access to Full Article Related Publications
Elevated expression of heat shock protein 5 (HSPA5) promotes drug resistance and metastasis and is a marker of poor prognosis in breast cancer patients. Adenovirus type 5 E1A gene therapy has demonstrated antitumor efficacy but the mechanisms of metastasis-inhibition are unclear. Here, we report that E1A interacts with p300 histone acetyltransferase (HAT) and blocks p300-mediated HSPA5 acetylation at K353, which in turn promotes HSPA5 ubiquitination by GP78 (E3 ubiquitin ligase) and subsequent proteasome-mediated degradation. Our findings point out the Ying-Yang regulation of two different post-translational modifications (ubiquitination and acetylation) of HSPA5 in tumor metastasis.

Song M, Yin Y, Zhang J, et al.
MiR-139-5p inhibits migration and invasion of colorectal cancer by downregulating AMFR and NOTCH1.
Protein Cell. 2014; 5(11):851-61 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) that exert function by posttranscriptional suppression have recently brought insight in our understanding of the role of non-protein-coding RNAs in carcinogenesis and metastasis. In this study, we described the function and molecular mechanism of miR-139-5p in colorectal cancer (CRC) and its potential clinical application in CRC. We found that miR-139-5p was significantly downregulated in 73.8% CRC samples compared with adjacent noncancerous tissues (NCTs), and decreased miR-139-5p was associated with poor prognosis. Functional analyses demonstrated that ectopic expression of miR-139-5p suppressed CRC cell migration and invasion in vitro and metastasis in vivo. Mechanistic investigations revealed that miR-139-5p suppress CRC cell invasion and metastasis by targeting AMFR and NOTCH1. Knockdown of the two genes phenocopied the inhibitory effect of miR-139-5p on CRC metastasis. Furthermore, the protein levels of the two genes were upregulated in CRC samples compared with NCTs, and inversely correlated with the miR-139-5p expression. Increased NOTCH1 protein expression was correlated with poor prognosis of CRC patients. Together, our data indicate that miR-139-5p is a potential tumor suppressor and prognostic factor for CRC, and targeting miR-139-5p may repress the metastasis of CRC and improve survival.

Shang Y, Zhu Z
gp78 is specifically expressed in human prostate cancer rather than normal prostate tissue.
J Mol Histol. 2013; 44(6):653-9 [PubMed] Related Publications
Elevated expression of gp78 has been observed in many types of cancers including lung, stomach, colon, liver and skin cancer. But there is no report about its expression in prostate cancers. In this study, using immunohistochemical staining we found gp78 is highly expressed in prostate cancers especially early stage tumors, but not in normal prostate tissues. gp78 protein expression is heterogeneous. In some tumors it was expressed in basal cells, while others in stromal cells. For gp78 is a ubiquitin E3 ligase, we then investigated the expression pattern of its cognate E2 (ubiquitin conjugating enzyme)-Ube2g2 in prostate cancers. We found it was expressed in both cancerous and normal tissues of prostate without significant differences in expression level. And unlike gp78, it exhibited a homogeneous expression pattern in different cell types in prostate tissues. In conclusion, our results indicate that gp78 is expressed specifically in human prostate cancer rather than normal prostate tissues, it could be a putative biomarker for prostate cancer diagnosis.

Choudhury Y, Tay FC, Lam DH, et al.
Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells.
J Clin Invest. 2012; 122(11):4059-76 [PubMed] Free Access to Full Article Related Publications
In the human brain, microRNAs (miRNAs) from the microRNA-376 (miR-376) cluster undergo programmed "seed" sequence modifications by adenosine-to-inosine (A-to-I) editing. Emerging evidence suggests a link between impaired A-to-I editing and cancer, particularly in high-grade gliomas. We hypothesized that disruption of A-to-I editing alters expression of genes regulating glioma tumor phenotypes. By sequencing the miR-376 cluster, we show that the overall miRNA editing frequencies were reduced in human gliomas. Specifically in high-grade gliomas, miR-376a* accumulated entirely in an unedited form. Clinically, a significant correlation was found between accumulation of unedited miR-376a* and the extent of invasive tumor spread as measured by magnetic resonance imaging of patient brains. Using both in vitro and orthotopic xenograft mouse models, we demonstrated that the unedited miR-376a* promoted glioma cell migration and invasion, while the edited miR-376a* suppressed these features. The effects of the unedited miR-376a* were mediated by its sequence-dependent ability to target RAP2A and concomitant inability to target AMFR. Thus, the tumor-dependent introduction of a single base difference in the miR-376a* sequence dramatically alters the selection of its target genes and redirects its function from inhibiting to promoting glioma cell invasion. These findings uncover a new mechanism of miRNA deregulation and identify unedited miR-376a* as a potential therapeutic target in glioblastoma cells.

Peer CJ, Sissung TM, Figg WD
CHIP and gp78-mediated ubiquitination of CYP3A4: Implications for the pharmacology of anticancer agents.
Cancer Biol Ther. 2011; 11(6):549-51 [PubMed] Free Access to Full Article Related Publications
The autocrine motility factor receptor or glycoprotein-78 (gp78) and C-terminus of Hsp70-interacting protein (CHIP) are E3-ligases required for ubiquitination of cytochrome P450s of the 3A subfamily (CYP3A) in endoplasmic reticulum-associated degradation (ERAD). The CYP isozyme 3A4 (CYP3A4) is responsible for the metabolism of the majority of xenobiotics including anticancer agents. Much variability in clinical response to chemotherapy is observed and it has been suggested that variability in CYP3A4 expression could be a factor. The study reviewed in this journal club comments on the importance of further characterizing gp78 and CHIP as relevant proteins in ERAD of CYP3A4. This study demonstrated how both gp78 and CHIP play direct roles in reducing CYP3A4 protein content as well as CYP3A4 ubiquitination. Interestingly, when gp78 and CHIP were knocked down by siRNAs directed towards each protein, the stabilized CYP3A4 remained functional. This has implications for drug-drug interactions for agents metabolized by CYP3A4, which can influence drug exposure levels. This is relevant because most anticancer agents have very narrow therapeutic windows, thus even slight changes in CYP3A4 levels could alter the exposure of that drug and result in either insufficient efficacy or toxicity. Future studies must explore genetic variability in the ERAD pathway and identify new factors that influence CYP3A ERAD in order to better characterize how CYP3A variability affects anticancer drug pharmacology.

Wei P, Milbauer LC, Enenstein J, et al.
Differential endothelial cell gene expression by African Americans versus Caucasian Americans: a possible contribution to health disparity in vascular disease and cancer.
BMC Med. 2011; 9:2 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Health disparities and the high prevalence of cardiovascular disease continue to be perplexing worldwide health challenges. This study addresses the possibility that genetic differences affecting the biology of the vascular endothelium could be a factor contributing to the increased burden of cardiovascular disease and cancer among African Americans (AA) compared to Caucasian Americans (CA).
METHODS: From self-identified, healthy, 20 to 29-year-old AA (n = 21) and CA (n = 17), we established cultures of blood outgrowth endothelial cells (BOEC) and applied microarray profiling. BOEC have never been exposed to in vivo influences, and their gene expression reflects culture conditions (meticulously controlled) and donor genetics. Significance Analysis of Microarray identified differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey nine biological systems relevant to endothelial biology.
RESULTS: At the highly stringent threshold of False Discovery Rate (FDR) = 0, 31 single genes were differentially expressed in AA. PSPH exhibited the greatest fold-change (AA > CA), but this was entirely accounted for by a homolog (PSPHL) hidden within the PSPH probe set. Among other significantly different genes were: for AA > CA, SOS1, AMFR, FGFR3; and for AA < CA, ARVCF, BIN3, EIF4B. Many more (221 transcripts for 204 genes) were differentially expressed at the less stringent threshold of FDR <.05. Using the biological systems approach, we identified shear response biology as being significantly different for AA versus CA, showing an apparent tonic increase of expression (AA > CA) for 46/157 genes within that system.
CONCLUSIONS: Many of the genes implicated here have substantial roles in endothelial biology. Shear stress response, a critical regulator of endothelial function and vascular homeostasis, may be different between AA and CA. These results potentially have direct implications for the role of endothelial cells in vascular disease (hypertension, stroke) and cancer (via angiogenesis). Also, they are consistent with our over-arching hypothesis that genetic influences stemming from ancestral continent-of-origin could impact upon endothelial cell biology and thereby contribute to disparity of vascular-related disease burden among AA. The method used here could be productively employed to bridge the gap between information from structural genomics (for example, disease association) and cell function and pathophysiology.

Grund S, Olsson B, Jernås M, et al.
The autocrine motility factor receptor is overexpressed on the surface of B cells in Binet C chronic lymphocytic leukemia.
Med Oncol. 2011; 28(4):1542-8 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a clinical spectrum reaching from discrete lymphocytosis to extensive enlargement of lymph nodes, spleen and liver, and bone marrow failure. The aim of this study was to identify genes that differentiate between patients with disease stage A vs. C according to Binet in order to better understand the disease. To achieve this, we performed DNA microarray analysis on B cells from CLL patients with stage A and C according to Binet and matched controls. Between CLL patients and controls, there were 1,528 differentially expressed genes and 360 genes were differentially expressed between Binet A and C patients. Due to the sheer number of regulated genes, we focused on the autocrine motility factor receptor (AMFR). AMFR has not previously been investigated in hematological disorders, but high expression of AMFR correlates with a more advanced stage and invasive potential in several human tumors. AMFR mRNA expression was higher in Binet A compared with Binet C patients (P=0.0053) and healthy controls (P=0.0051). Total AMFR protein was higher in Binet A patients compared to Binet C as analyzed by intracellular flow cytometry. However, AMFR exist both in the ER involved in protein degradation and on the cell surface involved in metastasis and cell motility. Cell surface AMFR was increased in Binet C compared with Binet A+B (P=0.016). In conclusion, the mRNA levels reflect the total amount of AMFR, whereas cell surface expression is associated with progression in CLL.

Joshi B, Li L, Nabi IR
A role for KAI1 in promotion of cell proliferation and mammary gland hyperplasia by the gp78 ubiquitin ligase.
J Biol Chem. 2010; 285(12):8830-9 [PubMed] Free Access to Full Article Related Publications
Expression of gp78, an E3 ubiquitin ligase in endoplasmic reticulum-associated degradation, is associated with tumor malignancy. To study gp78 overexpression in mammary gland development and tumorigenicity, we generated murine mammary tumor virus (MMTV) long terminal repeat-driven gp78 transgenic mice. Embryos carrying the gp78 transgene cassette were implanted in FVB surrogate mothers, and two founders with high copy integration showed elevated gp78 expression at both transcript and protein levels at the virgin stage and at 12 days gestation. Transgenic mammary glands showed increased ductal branching, dense alveolar lobule formation, and secondary terminal end bud development. Bromodeoxyuridine staining showed increased proliferation in hyperplastic ductal regions at the virgin stage and at 12 days gestation compared with wild type mice. Reduced expression of the metastasis suppressor KAI1, a gp78 endoplasmic reticulum-associated degradation substrate, demonstrates that gp78 ubiquitin ligase activity is increased in MMTV-gp78 mammary gland. Similarly, metastatic MDA-435 cells exhibit increased gp78 expression, decreased KAI1 expression, and elevated proliferation compared with nonmetastatic MCF7 cells whose proliferation was enhanced upon knockdown of KAI1. Importantly, stable gp78 knockdown HEK293 cells showed increased KAI1 expression and reduced proliferation that was rescued upon KAI1 knockdown, demonstrating that gp78 regulation of cell proliferation is mediated by KAI1. Mammary tumorigenesis was not observed in repeatedly pregnant MMTV-long terminal repeat-gp78 transgenic mice over a period of 18 months post-birth. Elevated gp78 ubiquitin ligase activity is therefore not sufficient for mammary tumorigenesis. However, the hyperplastic phenotype observed in mammary glands of MMTV-gp78 transgenic mice identifies a novel role for gp78 expression in enhancing mammary epithelial cell proliferation and nontumorigenic ductal outgrowth.

Chiu CG, St-Pierre P, Nabi IR, Wiseman SM
Autocrine motility factor receptor: a clinical review.
Expert Rev Anticancer Ther. 2008; 8(2):207-17 [PubMed] Related Publications
The ability to target and alter the metastatic activity of cancer cells is a key avenue for cancer therapeutics. While local tumor control is often achieved through surgical resection, patient morbidity and mortality is dependent upon the control of regional and distant spread of disease. Autocrine motility factor receptor (AMFR) is an internalizing cell surface receptor that also exhibits ubiquitin E3 ligase activity in the endoplasmic reticulum. Stimulation of AMFR by its ligand (autocrine motility factor/phosphoglucose isomerase) alters cellular adhesion, proliferation, motility, and apoptosis. Increased AMFR expression has been reported in numerous human cancer types. Review of these studies suggests that AMFR upregulation is significantly correlated with more advanced tumor stage and decreased survival for cancer of the lung, esophagus, stomach, colon, rectum, liver and skin. AMFR has also served as an independent predictor of poor disease prognosis in these tumor types. Significant associations between AMFR expression and other clinicopathologic parameters implicated in disease progression have also been reported. Further characterization of AMFR in human cancer and the development of an understanding of the molecular regulation of this protein is critical for its future role as a target for anticancer agents.

Tsai YC, Mendoza A, Mariano JM, et al.
The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation.
Nat Med. 2007; 13(12):1504-9 [PubMed] Related Publications
Metastasis is the primary cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. In particular, relatively little is known about metastasis in cancers of mesenchymal origins, which are known as sarcomas. Approximately ten proteins have been characterized as 'metastasis suppressors', but how these proteins function and are regulated is, in general, not well understood. Gp78 (also known as AMFR or RNF45) is a RING finger E3 ubiquitin ligase that is integral to the endoplasmic reticulum (ER) and involved in ER-associated degradation (ERAD) of diverse substrates. Here we report that expression of gp78 has a causal role in the metastasis of an aggressive human sarcoma and that this prometastatic activity requires the E3 activity of gp78. Further, gp78 associates with and targets the transmembrane metastasis suppressor, KAI1 (also known as CD82), for degradation. Suppression of gp78 increases KAI1 abundance and reduces the metastatic potential of tumor cells, an effect that is largely blocked by concomitant suppression of KAI1. An inverse relationship between these proteins was confirmed in a human sarcoma tissue microarray. Whereas most previous efforts have focused on genetic mechanisms for the loss of metastasis suppressor genes, our results provide new evidence for post-translational downregulation of a metastasis suppressor by its ubiquitin ligase, resulting in abrogation of its metastasis-suppressing effects.

Kojic LD, Joshi B, Lajoie P, et al.
Raft-dependent endocytosis of autocrine motility factor is phosphatidylinositol 3-kinase-dependent in breast carcinoma cells.
J Biol Chem. 2007; 282(40):29305-13 [PubMed] Related Publications
Autocrine motility factor (AMF) is internalized via a receptor-mediated, dynamin-dependent, cholesterol-sensitive raft pathway to the smooth endoplasmic reticulum that is negatively regulated by caveolin-1. Expression of AMF and its receptor (AMFR) is associated with tumor progression and malignancy; however, the extent to which the raft-dependent uptake of AMF is tumor cell-specific has yet to be addressed. By Western blot and cell surface fluorescence-activated cell sorter (FACS) analysis, AMFR expression is increased in tumorigenic MCF7 and metastatic MDA-231 and MDA-435 breast cancer cell lines relative to dysplastic MCF10A mammary epithelial cells. AMF uptake, determined by FACS measurement of protease-insensitive internalized fluorescein-conjugated AMF, was increased in MCF7 and MDA-435 cells relative to MCF-10A and caveolin-1-expressing MDA-231 cells. Uptake of fluorescein-conjugated AMF was dynamin-dependent, methyl-beta-cyclodextrin- and genistein-sensitive, reduced upon overexpression of caveolin-1 in MDA-435 cells, and increased upon short hairpin RNA reduction of caveolin-1 in MDA-231 cells. Tissue microarray analysis of invasive primary human breast carcinomas showed that AMFR expression had no impact on survival but did correlate significantly with expression of phospho-Akt. Phospho-Akt expression was increased in AMF-internalizing MCF7 and MDA-435 breast carcinoma cells. AMF uptake in these cells was reduced by phosphatidylinositol 3-kinase inhibition but not by regulators of macropinocytosis such as amiloride, phorbol ester, or actin cytoskeleton disruption by cytochalasin D. The raft-dependent endocytosis of AMF therefore follows a distinct phosphatidylinositol 3-kinase-dependent pathway that is up-regulated in more aggressive tumor cells.

Wang W, Yang LY, Yang ZL, et al.
Elevated expression of autocrine motility factor receptor correlates with overexpression of RhoC and indicates poor prognosis in hepatocellular carcinoma.
Dig Dis Sci. 2007; 52(3):770-5 [PubMed] Related Publications
Our previous study identified RhoC as an invasion and metastasis marker in hepatocellular carcinoma patients. Recent document suggested RhoGTPase is required for autocrine motility factor signaling. In this study, we questioned whether there is a correlation between expression of autocrine motility factor receptor and RhoC. Furthermore, we questioned whether elevated expression of autocrine motility factor correlates with metastasis and poor prognosis of HCC. The mRNA expression level of AMFR and RhoC were examined by RT-PCR in 25 cases of HCC and pericarcinomatous liver tissues (PCLT). In addition, the correlation between the expression level of AMFR and clinical pathologic parameters was analyzed. Furthermore, follow-up information was collected to evaluate the prognostic value of AMFR for HCC patients. Our results showed that the expression of AMFR and RhoC significantly increased in HCC compared with PCLT; extrahepatic metastatic lesions expressed significantly higher levels of AMFR and RhoC than corresponding intrahepatic HCC tissues. There is a highly significant correlation of AMFR expression levels with tumor vein invasion, number of tumor nodes, and tumor stage. Anticipatively, positive correlation was observed between mRNA expression of AMFR and RhoC gene. Furthermore, the HCC patients with high-expression of AMFR had significant high recurrence/metastasis and shorter survival than those with low-expression of AMFR. Together, our findings suggested a strong correlation between the expression of AMFR and RhoC and also a correlation between overexpression of them and invasion and metastasis of HCC. Furthermore, our data indicated AMFR as a potential prognosis for HCC.

Tanizaki Y, Sato Y, Oka H, et al.
Expression of autocrine motility factor mRNA is a poor prognostic factor in high-grade astrocytoma.
Pathol Int. 2006; 56(9):510-5 [PubMed] Related Publications
It has been reported that tumor infiltration is correlated with the expression of autocrine motility factor (AMF) and its receptor 78 kDa glycoprotein (gp78). The purpose of the present study was to detect AMF and gp78 mRNA expression levels and their localization in high-grade astrocytomas (glioblastoma and anaplastic astrocytoma) and to determine whether AMF and gp78 are important prognostic factors. A total of 32 formalin-fixed and paraffin-embedded glioblastomas and 23 formalin-fixed and paraffin-embedded anaplastic astrocytomas was used. The expressions of AMF and gp78 mRNA were detected using the highly sensitive in situ hybridization method. The expression of AMF mRNA was detected in 27 of 32 glioblastomas (84.4%) and 11 of 23 anaplastic astrocytomas (47.8%). The positivity of AMF mRNA was significantly higher in glioblastomas than in anaplastic astrocytomas (P = 0.0094), but gp78 mRNA was detected in most cases and no statistical significance was observed. The overall survival of patients with AMF expression was significantly shorter than patients without AMF expression (P = 0.0175). In anaplastic astrocytomas, the overall survival of patients with AMF expression was also significantly shorter than in patients without AMF expression (P = 0.0058). This study demonstrated that AMF is a poor prognostic factor in high-grade astrocytomas.

Hishizawa M, Imada K, Sakai T, et al.
Antibody responses associated with the graft-versus-leukemia effect in adult T-cell leukemia.
Int J Hematol. 2006; 83(4):351-5 [PubMed] Related Publications
Adult T-cell leukemia (ATL) is a peripheral T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). The prognosis of ATL, especially the acute and lymphoma subtypes, is poor with conventional and high-dose chemotherapy. The effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for ATL has been reported, suggesting the presence of a graft-versus-leukemia (GVL) effect against this malignancy. To identify the target antigens associated with tumor rejection, we used SEREX (serological identification of antigens by recombinant cDNA expression cloning) to screen ATL complementary DNA expression libraries with sera from an ATL patient who had a GVL response after allo-HSCT. Among the isolated clones, autocrine motility factor receptor (AMFR), which encodes a glycosylated transmembrane protein, was found to have selective reactivity with the sera obtained during tumor regression. Real-time reverse transcription polymerase chain reaction analysis for AMFR showed highest expression in the testis among normal tissues. Furthermore, aberrant AMFR expression was found in at least some ATL patients. Taken together, these findings suggest that AMFR may be one of the GVL antigens that provoke effective antitumor immunity against ATL in allogeneic settings.

Guenther R, Krenn V, Morawietz L, et al.
Giant cell tumors of the bone: molecular profiling and expression analysis of Ephrin A1 receptor, Claudin 7, CD52, FGFR3 and AMFR.
Pathol Res Pract. 2005; 201(10):649-63 [PubMed] Related Publications
Giant cell tumors (GCTs) of the bone are osteolytic neoplasms with variable degrees of aggressiveness. The aim of this study was the molecular characterization of GCT tissue. We established gene expression profiles and discovered a number of genes that have not been described in GCTs before. RNA was prepared from 7 cryopreserved GCTs (primary tumors n = 5, relapses n = 2) and was hybridized to Affymetrix HG U133A microarrays. Paraffin-embedded samples were used for immunohistochemical validation (primary tumors n = 16, relapses n = 6). Gene ontology revealed that the majority of genes, found to be differentially expressed between primary and recurrent GCTs, were associated with receptor tyrosine kinase activity. We selected one upregulated gene (Claudin 7) and four downregulated genes (CD52, Ephrin A1 receptor, autocrine motility factor receptor [AMFR] and fibroblast growth factor receptor 3 [FGFR3] for further analysis using immunohistochemistry. Immunohistochemical analysis of CD52, AMFR, and Ephrin A1 receptor revealed expression profiles concordant with the microarray data, also with regard to differences between primary tumors and relapses.

Yanagawa T, Funasaka T, Tsutsumi S, et al.
Novel roles of the autocrine motility factor/phosphoglucose isomerase in tumor malignancy.
Endocr Relat Cancer. 2004; 11(4):749-59 [PubMed] Related Publications
Autocrine motility factor (AMF) stimulates cell motility in an autocrine manner and is related to tumor malignancy. AMF is a multifunctional molecule, also known as phosphoglucose isomerase and neuroleukin. Signal cascades of the AMF-stimulated motility and novel functions of this protein contributing to tumor malignancy have been presented recently. AMF stimulation activated small Rho-like GTPases and subsequently induced actin fiber rearrangement, which was removed by the C3 exoenzyme, a specific inhibitor of Rho. The expression of Jun N-terminal kinase (JNK)1, JNK2 and the Rho GDP dissociation inhibitor-beta was upregulated by AMF. The addition of AMF to culture medium stimulated the motility of the endothelial cells and the formation of tube-like structures in collagen gels. Highly AMF-expressing HT1080 cells induced aggressive angiogenesis in vivo. The expression of fms-like tyrosine kinase (Flt)-1, a vascular endothelial growth factor (VEGF) receptor, was enhanced in AMF-expressing tumors dependent on protein kinase C and phosphatidylinositol 3 kinase (PI3K) activation; meanwhile kinase insert domain-containing receptor, another receptor of VEGF, was not. Permeability of mesothelial and endothelial cell monolayers was increased by AMF, and numerous gaps were observed in the monolayers after treatment with AMF. AMF gene transfection transformed NIH3T3 cells to proliferate quickly and acquire anti-apoptosis ability induced by serum deprivation in a PI3K-dependent manner. The anti-apoptotic effect of AMF has been described by other authors who have shown that the AMF over-expressing cells were resistant to mitomycin-C-induced apoptosis showing regression of Apaf-1 and caspase-9 dependent on PI3K and MAP kinase. These novel functions of AMF makes it a likely target for cancer therapy.

Takanami I, Inoue Y, Gika M
G-protein inwardly rectifying potassium channel 1 (GIRK 1) gene expression correlates with tumor progression in non-small cell lung cancer.
BMC Cancer. 2004; 4:79 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: G-protein inwardly rectifying potassium channel 1 (GIRK1) is thought to play a role in cell proliferation in cancer, and GIRK1 gene expression level may define a more aggressive phenotype. We detected GIRK1 expression in tissue specimens from patients with non-small cell lung cancers (NSCLCs) and assessed their clinical characteristics.
METHODS: Using reverse transcription-polymerase chain reaction (RT-PCR) analyses, we quantified the expression of GIRK1 in 72 patients with NSCLCs to investigate the relationship between GIRK1 expression and clinicopathologic factors and prognosis.
RESULTS: In 72 NSCLC patients, 50 (69%) samples were evaluated as having high GIRK1 gene expression, and 22 (31%) were evaluated as having low GIRK1 gene expression. GIRK1 gene expression was significantly associated with lymph node metastasis, stage (p = 0.0194 for lymph node metastasis; p = 0.0207 for stage). The overall and stage I survival rates for patients with high GIRK1 gene expressed tumors was significantly worse than for those individuals whose tumors had low GIRK1 expression (p = 0.0004 for the overall group; p = 0.0376 for stage I).
CONCLUSIONS: These data indicate that GIRK1 may contribute to tumor progression and GIRK1 gene expression can serve as a useful prognostic marker in the overall and stage I NSCLCs.

Takanami I, Takeuchi K
Autocrine motility factor-receptor gene expression in lung cancer.
Jpn J Thorac Cardiovasc Surg. 2003; 51(8):368-73 [PubMed] Related Publications
OBJECTIVE: Autocrine motility factor (AMF) stimulates cell motility via binding its receptor (AMF-R) and AMF-R is engaged in tumor cell motility and the AMF-R gene expression level may define a more aggressive phenotype. In this study, we investigated the expression of AMF-R in lung cancer cells and revealed its roles in the cell motility of a tumor. We detected AMF-R expression in tissue specimens from patients with non-small cell lung cancers (NSCLCs) and assessed their clinical characteristics.
METHODS: Using reverse transcription-polymerase chain reaction (RT-PCR) analyses and phagokinetic assay, we studied the correlation between the level of AMF-R gene expression and cell motility. We quantified the expression of AMF-R in 51 patients with NSCLCs to investigate the relationship between AMF-R expression and clinicopathologic factors and prognosis.
RESULTS: We found that lung cancer cell lines with higher AMF-R gene expression tended to have larger cell motility than those with lower AMF-R gene expression. The AMF-R gene expression was significantly associated with lymph node metastasis, and stage. The overall survival rate for patients with a high level of AMF-R gene expression with tumors was significantly worse than for those individuals whose tumors had low AMF-R expression. Furthermore, AMF-R expression was significantly related to survival by multivariate analysis.
CONCLUSION: These data indicate that AMF-R may contribute to tumor progression and AMF-R gene expression can serve as a useful prognostic marker in NSCLCs.

Fang S, Lorick KL, Jensen JP, Weissman AM
RING finger ubiquitin protein ligases: implications for tumorigenesis, metastasis and for molecular targets in cancer.
Semin Cancer Biol. 2003; 13(1):5-14 [PubMed] Related Publications
Covalent modification of proteins with ubiquitin regulates almost all aspects of eukaryotic cellular function. Ubiquitin protein ligases (E3s) play central regulatory roles in that they provide substrate specificity to this process and therefore, represent attractive molecular targets for disease therapy. We summarize recent advances in our understanding of RING finger and RING finger-related E3s with emphasis on BRCA1 and the tumor autocrine motility factor receptor (gp78), as well as discuss the potential for components of the ubiquitin pathway for proteasomal degradation as molecular targets.

Niizeki H, Kobayashi M, Horiuchi I, et al.
Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells.
Br J Cancer. 2002; 86(12):1914-9 [PubMed] Free Access to Full Article Related Publications
The incidence of distant metastases is higher in the tumours with low oxygen pressure than in those with high oxygen pressure. It is well known that hypoxia induces the transcription of various genes involved in angiogenesis and anaerobic metabolism necessary for the growth of tumour cells in vivo, suggesting that hypoxia may also induce the transcription of metastasis-associated genes. We sought to identify the metastasis-associated genes differentially expressed in tumour cells under hypoxic conditions with the use of a DNA microarray system. We found that hypoxia enhanced the expression of autocrine motility factor mRNA in various cancer cells and also enhanced the random motility of pancreatic cancer cells. Autocrine motility factor inhibitors abrogated the increase of motility under hypoxic conditions. In order to explore the roles of hypoxia-inducible factor-1alpha, we established hypoxia-inducible factor-1alpha-transfectants and dominant negative hypoxia-inducible factor-1alpha-transfectants. Transfection with hypoxia-inducible factor-1alpha and dominant-negative hypoxia-inducible factor-1alpha enhanced and suppressed the expression of autocrine motility factor/phosphohexase isomerase/neuroleukin mRNA and the random motility, respectively. These results suggest that hypoxia may promote the metastatic potential of cancer cells through the enhanced autocrine motility factor/phosphohexase isomerase/neuroleukin mRNA expression and that the disruption of the hypoxia-inducible factor-1 pathway may be an effective treatment for metastasis.

Funasaka T, Haga A, Raz A, Nagase H
Tumor autocrine motility factor induces hyperpermeability of endothelial and mesothelial cells leading to accumulation of ascites fluid.
Biochem Biophys Res Commun. 2002; 293(1):192-200 [PubMed] Related Publications
Accumulation of ascites fluid often observed in some solid tumors is one of the most devastating conditions of a patient's difficulty in responding to treatment, and to a decrease in the quality of life. Various factors are thought to be associated with the formation of cancer-induced fluid accumulation and hyperpermeability of a blood vessel is thought to go with this process. Here, we report a new factor that is involved in this process, e.g., autocrine motility factor (AMF). AMF is a tumor-related cytokine which stimulates the tumor cell locomotion and migration and promotes tumor cell invasion during metastasis. AMF secretion and its receptor (AMFR) expression in tumor cells are closely correlated with disease aggravation of convalescence. The response of endothelial or mesothelial cellular morphological alternation to AMF leads to motile enhancement and vascular permeability. Tumor AMF induces gaps in an endothelial or mesothelial monolayer by stimulating a cellular movement, and accelerates the ascites accumulation. And treatment experiment with anti-AMF antibody succeeded in the reduction of the ascites accumulation, which renders AMF to the target molecule. It is suggested that AMF is one of the significant factors which relates to various pathological malignancies induced by tumor mass, and understanding of its function could benefit prognosis and treatment.

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