Amphiregulin and Epiregulin Expression in Colorectal Carcinoma and the Correlation with Clinicopathological Characteristics

Li, Xiaodong; Miao, Shuying; Wang, Guoliang; Yang, Li; Shu, Yongqian; Yin, Yongmei

doi:10.1159/000315380

Cited by 37 publications

(31 citation statements)

References 23 publications

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“…In the present work we suggest that immunocytochemistry of pERK1/2 can be considered as a useful marker for early diagnosis, which may lead to more accurate treatment of the cancer and to improved prognosis. Internalization of pERK1/2 into the nucleus occurs since growth factors of the family of EGF and their receptors are produced in the colon cancer cells (10). These growth factors are cleaved by methaloproteinase, which binds and activates the receptor to EGF (12).…”

Section: Discussionmentioning

confidence: 99%

“…It was also speculated that UCP2 altered suppression, oxidative stress and NF-κB activation could be related to successive events in cancer development, including colon cancer (9). Moreover, expression of epiregulin and KRAS mutation was found valuable in predicting control of metastatic colorectal cancer, using specific drugs as Cetaxumab (4,10). High expression of ERBB1, ERBB 2 and ERBB3, but not ERBB4 were found in colon cancer cell lines and could help in the selection of the appropriate chemotherapy (7,11).…”

Section: Introductionmentioning

confidence: 99%

“…High expression of ERBB1, ERBB 2 and ERBB3, but not ERBB4 were found in colon cancer cell lines and could help in the selection of the appropriate chemotherapy (7,11). High serum and tissue levels of amphiregulin and high tissue level of epiregulin were suggested to be predictors of a poor prognosis in patients with colorectal carcinoma (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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Two initiation sites of early detection of colon cancer, revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of tumor cells

et al. 2011

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Abstract.We have used human specimens and antibodies to pERK1/2 to detect early development of colon cancer, using indirect immunocytochemistry. Two distinct sites were stained; one at the tip of the colon villi and the other in the stromal tissue, associated with the colon tissue. These foci represent early stages of colon cancer initiation, as established by enhanced KRAS, and lack of p53 staining. It should be noted, however, that the enhanced KRAS coincides with the initiation of tumor growth revealed by pERK1/2 only in the tip of the colon villi but not in the stromal initiation site of the colon tumors. Interestingly, foci of pERK1/2 staining were also detected within 50% of stromal tissue and tips of colon villi, that were classified as normal tissues, distal from the malignant one according to general morphology. The staining of pERK1/2 at the stromal foci of this apparently non-malignant tissue appeared as aggregates at the perinuclear region, while at the colon epithelium, it appeared at the cell nuclei. At low-grade of colon cancer, that was still free of induced mutated p53, staining of pERK1/2 was prominent at the cell nuclei both at the stroma tissue and the tip of the colon villi. In intermediate stage, that exhibited a significant p53 staining, only a fraction of p53-free tumor cells was labeled with pERK1/2 antibody, while in high-grade tumors, all cells of tumors were labeled with antibodies to p53, but not with pERK1/2. We also found that the cytoplasm of low-grade tumors was positive for epiregulin, while this labeling decreased in high-grade tumors. Interestingly, we found that the tumors initiating from the stroma demonstrated poor structural differentiation, while the tumors initiating from the epithelial cells of the colon demonstrated high structural differentiation. It is concluded that pERK1/2 is a sensitive early marker of colon cancer, which disappears at later stages of cancer development. Moreover, pERK1/2 staining can distinguish between tumor cells originated from the tip of the colon villi and those originated in the stroma, associated with the colon tissue, and thus can assist in selecting the appropriate therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Two initiation sites of early detection of colon cancer, revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of tumor cells

et al. 2011

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“…They also showed that knockdown of AREG by specific siRNAs in HCC cells inhibited cell growth and reduced their ability to resist apoptosis (13). In addition, in colorectal cancer, AREG-positive status was shown to be significantly correlated with tumor invasion depth, distant metastases, and nerve invasion, indicating an association between AREG levels and invasive growth (16). Moreover, previous clinical research supporting the role of AREG in cancer development and progression showed that AREG might serve as a prognostic and/or a predictive biomarker (17,18).…”

Section: Introductionmentioning

confidence: 97%

RASSF1A-Mediated Regulation of AREG via the Hippo Pathway in Hepatocellular Carcinoma

Ahn

Kim

et al. 2013

Molecular Cancer Research

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Ras association domain family 1 isoform A (RASSF1A) is a tumor suppressor that is methylated in many human cancers, including hepatocellular carcinoma (HCC). RASSF1A has been shown to suppress tumors via activation of the Hippo tumor suppressor pathway, including mammalian STE20-like kinase (MST). Amphiregulin (AREG), a target gene for Yes-associated protein (YAP), is a known oncogenic component of the Hippo pathway; however, the tumor-suppressive effect of RASSF1A on AREG in regard to regulation of the Hippo pathway remains unclear in HCC. Overexpression of RASSF1A in HCC cells, which lack functional RASSF1A, significantly inhibited cell proliferation and induced apoptosis by activating the Hippo pathway. Consequently, overexpression of RASSF1A inhibited the oncogenic functions of YAP, leading to a significant reduction in AREG secretion via regulation of the Hippo pathway. In human specimens, greater expression of RASSF1A was observed in chronic hepatitis/cirrhosis than in HCC, whereas expression of YAP and AREG was higher in 81% and 86% of HCC than in corresponding chronic hepatitis/cirrhosis, respectively. Furthermore, RASSF1A protein gradually decreased as multistep hepatocarcinogenesis progressed from chronic hepatitis/ cirrhosis dysplastic nodules toward HCC, whereas the protein expression of YAP and AREG gradually increased. These findings provide mechanistic insight into the regulation of YAP and AREG by RASSF1A in human multistep hepatocarcinogenesis. Mol Cancer Res; 11(7); 748-58. Ó2013 AACR. IntroductionHepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death (1). Recently, several genetic and epigenetic alterations were shown to be related with hepatocarcinogenesis, including frequent promoter hypermethylation of several tumor suppressor genes, such as Ras association domain family 1 isoform A (RASSF1A; ref. 2). In HCC, epigenetic alterations, such as global DNA hypomethylation or CpG island hypermethylation, are critical mechanisms that affect the loss and gain of DNA methylation, respectively (3). Accordingly, inactivation of RASSF1A by DNA methylation has been shown to be involved in the development of many human cancers,

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“…Elevated levels of amphiregulin have been characterized in various types of tumors, and amphiregulin is assumed to play a role in promoting cancer progression (9,10). Amphiregulin also elevates angiogenic activity, promoting tumor growth and metastasis in pancreatic, colorectal, liver, and lung cancers (9)(10)(11)(12). A recent study has indicated that cancer-derived ATP increased the expression of amphiregulin in DCs in a mouse lung cancer cell line (13).…”

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confidence: 99%

Lung Tumor-Associated Dendritic Cell-Derived Amphiregulin Increased Cancer Progression

Hsu

Huang

Cheng

et al. 2011

The Journal of Immunology

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The interaction of cancer within a microenvironment is an important factor determining cancer development. This study analyzed the soluble factors secreted by tumor-associated dendritic cells (TADCs), which are responsible for increasing lung cancer growth, migration, invasion, and epithelial-to-mesenchymal transition. Addition of amphiregulin, present in large amounts in TADC-conditioned medium (CM), mimicked the inductive effect of TADC-CM on lung cancer progression, supported by the enhancement of cell proliferation, migration, and invasion as well as osteolytic bone metastases phenotypes. In contrast, neutralization of amphiregulin from TADC-CM decreased the advanced malignancy-inductive properties of TADC-CM. Significant upregulation of amphiregulin has been seen in tumor-infiltrating CD11c+ DCs in human lung cancer samples and patients’ sera. The enhancement of amphiregulin in TADCs has also been noted in mice transplanted with lung cancer cells. Induction of lung cancer progression by TADC-derived amphiregulin is associated with increased STAT3 and AKT activation, which subsequently increases the expression of cyclin D, Twist, and Snail. Blocking AKT significantly decreases TADC-CM and amphiregulin-mediated migration by decreasing the upregulation of Snail, whereas inhibition of STAT3 reduced the modulation of TADC-derived amphiregulin on Twist and cyclin D expression, suggesting that cooperation of STAT3 and AKT plays a critical role in TADC-mediated cancer progression. Moreover, mice treated with anti-amphiregulin Abs showed decreased incidence of cancer development and increased survival rates. Our study suggests that inhibition of amphiregulin or amphiregulin-related signaling is an attractive therapeutic target in lung cancer patients.

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Amphiregulin and Epiregulin Expression in Colorectal Carcinoma and the Correlation with Clinicopathological Characteristics

Cited by 37 publications

References 23 publications

Two initiation sites of early detection of colon cancer, revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of tumor cells

Two initiation sites of early detection of colon cancer, revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of tumor cells

RASSF1A-Mediated Regulation of AREG via the Hippo Pathway in Hepatocellular Carcinoma

Lung Tumor-Associated Dendritic Cell-Derived Amphiregulin Increased Cancer Progression

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