HER-2 and HER-3 expression in liver metastases of patients with colorectal cancer

Styczen, Hanna; Nagelmeier, Iris; Beißbarth, Tim; Nietert, M.; Homayounfar, Kia; Sprenger, Thilo; Boczek, Ute; Stanek, Kathrin; Kitz, Julia; Wolff, Hendrik A.; Ghadimi, Michael; Middel, Peter; Liersch, Torsten; Rüschoff, Josef; Conradi, Lena‐Christin

doi:10.18632/oncotarget.3527

Cited by 23 publications

(26 citation statements)

References 53 publications

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“…Although ERBB2 has been described to have oncogenic properties, we demonstrated that expression was significantly down-regulated in UC patients who harbored neoplastic lesions. This is consistent with findings from previous studies which concluded that a low percentage of sporadic colon cancers are HER2 positive as well as a recently published analysis that identified a low rate of ERBB2-activating mutations in IBD-associated neoplasia (41–43). …”

Section: Discussionsupporting

confidence: 93%

miR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis-associated Colorectal Neoplasia Through Regulation of Focal Adhesion Signaling

Pekow

Hutchison

Meckel

et al. 2017

Inflammatory Bowel Diseases

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Background As mechanisms of neoplasia in patients with ulcerative colitis (UC) remain poorly understood, we sought to identify pathways of carcinogenesis in this high-risk population. Methods miRNA and mRNA expression was examined in non-dysplastic rectosigmoid mucosa from UC patients with (n=19) or without remote colon neoplasia (n=23). We developed a method to identify miRNA-regulated pathways based on differentially expressed miRNAs and their putative mRNAs targets in the same samples. One key pathway identified in the analysis, miR-4728-3p regulation of focal adhesion signaling, was further evaluated in vitro as well as through examination of expression in UC-cancers. Results There were 101 significantly down-regulated and 97 up-regulated miRNAs (adjusted p<0.05) in the rectal mucosa of UC patients harboring proximal neoplasia. Bioinformatic analysis identified miR-4728-3p as a regulator of 3 proteins involved in focal adhesion signaling, CAV1, THBS2, and COL1A2. Real-time PCR validated down-regulation of miR-4728-3p in non-dysplastic tissue remote from UC-neoplasia as well as in UC-associated colon cancers. miR-4728-3p transfection into colon cancer cells down-regulated expression levels and decreased luciferase activities in cells expressing a wild type 3′ UTR compared to a mutant 3′ UTR for all three genes. Exogenous transfected miR-4728-3p also delayed wound healing and decreased formation of focal adhesion complexes. Conclusions Patients with long-standing UC who harbor neoplasia can be identified based on miRNA and mRNA profiles in non-dysplastic tissue. Using a method to analyze miRNA and mRNA expression from the same tissues, we identified that miR-4728-3p is likely an important tumor-suppressor in UC-associated colon carcinogenesis.

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Section: Discussionsupporting

confidence: 93%

miR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis-associated Colorectal Neoplasia Through Regulation of Focal Adhesion Signaling

Pekow

Hutchison

Meckel

et al. 2017

Inflammatory Bowel Diseases

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“…However, the role and regulatory mechanisms of HER3 in CRC cells remain unclear. Preclinical studies reported that HER3 is expressed in more than 75% of CRC primary and metastatic tumors (34,35), and its overexpression mediates CRC cell resistance to anti-EGFR therapy (36–38).…”

Section: Discussionmentioning

confidence: 99%

Endothelial Cells Promote Colorectal Cancer Cell Survival by Activating the HER3-AKT Pathway in a Paracrine Fashion

Wang

Bhattacharya

et al. 2019

Molecular Cancer Research

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The regulation of colorectal cancer cell survival pathways remains to be elucidated. Previously, it was demonstrated that endothelial cells (EC) from the liver (liver parenchymal ECs or LPEC), the most common site of colorectal cancer metastases, secrete soluble factors in the conditioned medium (CM) that, in turn, increase the cancer stem cell phenotype in colorectal cancer cells. However, the paracrine effects of LPECs on other colorectal cancer cellular functions have not been investigated. Here, results showed that CM from LPECs increased cell growth and chemoresistance by activating AKT in colorectal cancer cells Using an unbiased receptor tyrosine kinase array, it was determined that human epidermal growth factor receptor 3 (ERBB3/HER3) was activated by CM from LPECs, and it mediated AKT activation, cell growth, and chemoresistance in colorectal cancer cells. Inhibition of HER3, either by an inhibitor AZD8931 or an antibody MM-121, blocked LPEC-induced HER3-AKT activation and cell survival in colorectal cancer cells. In addition, CM from LPECs increased tumor growth in a xenograft mouse model. Furthermore, inhibiting HER3 with AZD8931 significantly blocked tumor growth induced by EC CM. These results demonstrated a paracrine role of liver ECs in promoting cell growth and chemoresistance via activating HER3-AKT in colorectal cancer cells. This study suggested a potential of treating patients with metastatic colorectal cancer with HER3 antibodies/inhibitors that are currently being assessed in clinical trials for various cancer types.

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“…The remaining 32 articles were screened for titles and abstracts, of which 24 were excluded (19 articles with insufficient data and 5 with methods other than IHC to evaluate the Her3 status). Finally, 8 studies [ 14 – 17 , 19 – 22 ] were included in this meta-analysis. In these studies, the proportion of Her3 overexpression ranged from 13.4% to 80.3%, and the proportion of high Her3 expression in all patients was 65.9% (1131/1716).…”

Section: Resultsmentioning

confidence: 99%

“…Table 1 summarizes the cut-off for Her3 overexpression and clinicopathological factors. Her3 expression in 6 studies [ 15 – 17 , 19 – 20 , 22 ] was graded as follows: grade 0 to 1 was categorized as low expression and grade 2 to 3 as high expression. Furthermore, 2 studies [ 14 , 21 ] were evaluated according to the Rajkumar score, and the specificity for estimating Her-3 expression was set at ≤8.…”

Section: Resultsmentioning

confidence: 99%

“…The study quality score ranged from 5 to 8, and articles with a score of ≥6 were regarded as having high quality. Among the articles, 5 studies [ 12 – 14 , 16 – 17 ] compared the association between Her3 overexpression and tumor differentiation, 4 [ 15 , 19 , 20 , 22 ] reported the asscociation between high Her3 expression and TNM stage, 4 [ 16 , 17 , 20 , 22 ] assessed the distribution of Her3 overexpression in left- and right-sided colon cancers, 5 [ 15 , 17 , 19 , 20 , 22 ] analyzed the distribution of Her3 overexpression at the site of colon or rectal cancer, 3 [ 15 , 16 , 20 ] compared the difference in Her3 overexpression between patients aged 66 and >66 years, 2 [ 14 , 21 ] reported tumor response in case of high and low Her3 expression, 6 [ 14 – 16 , 19 , 21 , 22 ] compared OS between patients with high and low Her3 expression, and 3 [ 15 , 20 , 21 ] mentioned HR and 95% CIs. The remaining studies [ 14 , 19 , 22 ] were assessed using Engauge Digitizer 4.1 through survival curves.…”

Section: Resultsmentioning

confidence: 99%

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Association between the overexpression of Her3 and clinical pathology and prognosis of colorectal cancer

et al. 2018

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Background:This study aimed to investigate the association between the overexpression of human epidermal growth factor receptor-3 (Her3) and the clinicopathological parameters and survival of patients with colorectal cancer (CRC).Methods:Relevant studies on the overexpression of Her3 (measured by immunohistochemistry) and overall survival (OS) in patients with CRC were searched for in PubMed, EMBASE, and Cochrane Library. Published data were extracted and computed into odds ratios (ORs) for assessing the association of Her3 overexpression with tumor differentiation, tumor node metastasis (TNM) stage, position of colon cancer, sex, and age. Prognostic data were computed into hazard ratios (HRs) for OS.Results:Eight studies including 1716 patients with CRC were included in this meta-analysis. The results revealed a significant association between Her3 overexpression and tumor differentiation [OR = 2.38; 95% confidence interval (95% CI): 1.76–3.22; P < .001], TNM tumor stage (OR = 0.71; 95% CI: 0.53–0.96; P = .03), and position of colon cancer (OR = 1.71; 95% CI: 1.28–2.27; P < .001). While patients with Her3 overexpression demonstrated a worse tumor response (OR = 0.31; 95% CI: 0.16–0.60; P < .001) and OS after treatment with cetuximab (HR = 1.86; 95% CI: 1.24–2.79; P = .003), they demonstrated better OS after symptomatic treatment (HR = 0.65; 95% CI: 0.50–0.85; P = .002). Her3 overexpression was not associated with sex (OR = 1.03; 95% CI: 0.83–1.28; P = .79), age (OR = 0.96; 95% CI: 0.75–1.24; P = .77), colon or rectum site (OR = 0.79; 95% CI: 0.44–1.43; P = .44), and total OS (HR = 1.09; 95% CI: 0.69–1.72; P = .72).Conclusion:Her3 expression is associated with the clinical pathology and prognosis of CRC, which explains the nonefficacy of cetuximab treatment in patients with CRC.

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HER-2 and HER-3 expression in liver metastases of patients with colorectal cancer

Cited by 23 publications

References 53 publications

miR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis-associated Colorectal Neoplasia Through Regulation of Focal Adhesion Signaling

miR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis-associated Colorectal Neoplasia Through Regulation of Focal Adhesion Signaling

Endothelial Cells Promote Colorectal Cancer Cell Survival by Activating the HER3-AKT Pathway in a Paracrine Fashion

Association between the overexpression of Her3 and clinical pathology and prognosis of colorectal cancer

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