Upregulation of discoidin domain receptor 2 in nasopharyngeal carcinoma

Chua, Huey Huey; Yeh, Te‐Huei; Wang, Ying‐Piao; Huang, Yu Chuan; Sheen, Tzung Shiahn; Lo, You Chang; Chou, Yeh‐Pin; Tsai, Ching Hwa

doi:10.1002/hed.20724

Cited by 31 publications

(26 citation statements)

References 33 publications

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“…Chua et al reported that DDR2 expression in both primary and metastatic tissues of nasopharyngeal carcinoma (NPC) was significantly higher than in other HNSCC and nasopharyngeal lymphoid hyperplasia tissues. 21 This is consistent with the conclusion from our current study since 98% of the NPC specimens are high-grade cases. 22 Therefore, it is supposed that DDR2 might act as a hallmark of highgrade and metastatic HNSCC.…”

Section: Discussionsupporting

confidence: 93%

Overexpression of DDR2 contributes to cell invasion and migration in head and neck squamous cell carcinoma

Lü

Zhang

et al. 2014

Cancer Biology & Therapy

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IntroductionHead and neck squamous cell carcinoma (HNSCC) represents approximately 6% of all cancers and about 500 000 cases are diagnosed every year.1 Over the past 20 years, diagnosis and management of HNSCC have improved through combined efforts in surgery, radiotherapy and chemotherapy, but the overall 5-y survival rate for patients is still only 40-50%. 2 The high rate of recurrence of HSNCC and its significant metastatic potential after conventional therapy appear to be major contributing factors for restricted survival of HNSCC patients.3 Therefore, understanding the molecular cancer pathways of underlying HNSCC metastasis would help to improve the therapy of the disease.Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase (RTK) that can be activated by fibrillar collagens, 4-6 and implicated in several cancer cell behaviors, including VEGF expression, tumor angiogenesis, invasion, and metastasis. [7][8][9] Matrix metalloproteinases (MMPs) are an important subset of downstream target genes of DDR2 signaling. 10,11 EMT plays an important role in the metastasis of HNSCC by facilitating primary tumor invasion through the basement membrane and migration through the tumor-associated stroma or extracellular matrix (ECM).12-14 It has been reported that DDR2 is a critical regulator of EMT.15 Though previous studies have investigated the function of DDR2 in some common tumors, there has not been functional characterization of the potential role of DDR2 in HNSCC. Therefore, the aim of the current study was to investigate this issue. Results DDR2 is highly expressed in high-grade HNSCCIn order to explore the role of DDR2 in HNSCC, we first compared its expression levels in non-cancerous and cancer tissues. The results of real-time quantitative PCR (qPCR) showed that the mRNA expression level of DDR2 was much higher in all the tumor tissues than in their normal counterparts, and Keywords: DDR2, HNSCC, tumor metastasis, EMT, hypoxiaBackground: Discoidin domain receptor 2 (DDR2) is a unique receptor tyrosine kinase (RTK) that is activated by fibrillar collagens. although DDR2 contributes to the metastasis of some tumors, its role in head and neck squamous cell carcinoma (hNsCC) remains unknown. The aim of this study was to investigate the expression level, clinical and pathological significance, and biologic function of DDR2 in hNsCC.Methods: Real-time quantitative PCR, western blot, and immunohistochemical staining were employed to assess the expression levels of DDR2 in hNsCC specimens. adenovirus-mediated overexpression of DDR2 was used to evaluate its consequences on cell proliferation, invasion, migration, and the process of hypoxia-induced epithelial-mesenchymal transition (eMT). Then nude mouse xenograft and tail vein metastasis models were utilized to validate the in vitro results.Results: DDR2 was highly expressed in high grade hNsCC tissues and lowly expressed in low grade hNsCC tissues, but absent or rarely expressed in cancer-associated normal tissues. Both the frequency and expression intensit...

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Section: Discussionsupporting

confidence: 93%

Overexpression of DDR2 contributes to cell invasion and migration in head and neck squamous cell carcinoma

Lü

Zhang

et al. 2014

Cancer Biology & Therapy

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“…This is consistent with the observation that DDR1 transcripts are upregulated in NPC, NPC metastasis, and head and neck tumor tissues (7). Furthermore, these results are consistent with a previous study that reported that inhibition of DDR1 by siRNA suppressed tumorigenicity, inhibited lung cancer bone metastasis and increased cancer cell chemosensitivity (24).…”

Section: Discussionsupporting

confidence: 93%

“…DDRs, which are distinguished from other RTKs by the discoidin motif in their extracellular domain (5), are upregulated in a number of solid tumors, including head and neck cancer, and nasopharyngeal, breast, ovarian and esophageal carcinomas (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). According to the homology of the C-terminal region, DDRs may be divided into two categories: DDR1 and DDR2.…”

Section: Introductionmentioning

confidence: 99%

Antitumor activity of 7RH, a discoidin domain receptor 1 inhibitor, alone or in combination with dasatinib exhibits antitumor effects in nasopharyngeal carcinoma cells

Chen

Peng

et al. 2016

Oncology Letters

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“…DDR2 was mutated in 3–4% of squamous cell cancers of the lung [6], amplified in 10.4% and mutated in 2.2% adenocarcinomas of lung [31], amplified in 29% of neuroendocrine prostatic cancers [32], advanced prostatic adenocarcinomas [33], advanced hepatocellular carcinomas [34], nasopharyngeal cancers [35], amplified in 12.6% and mutated in 0.7% of invasive carcinomas of breast [36], and amplified in 10.1% of pancreatic adenocarcinomas [37]. Pure mutated DDR2 without evidence of an altered copy number was reported in a few malignancies including 13.8% of cutaneous squamous cell carcinomas [38], 6.9% of small cell lung cancers [39], 4.5% of uterine carcinosarcomas [40], and 4.1% of cutaneous melanomas [41].…”

Section: Discussionmentioning

confidence: 99%

DDR2 overexpression in urothelial carcinoma indicates an unfavorable prognosis: a large cohort study

Tsai

Huang

et al. 2016

Oncotarget

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The migration ability of urothelial carcinoma corresponding to dismal prognosis had not been fully investigated. The interaction of extracellular collagen with a unique transmembrane receptor tyrosine kinase, Discoidin domain receptor 2 (DDR2), was selected by data mining. We arranged real-time reverse transcription polymerase chain reaction assays to evaluate the transcript levels in 26 urinary tract urothelial carcinoma and 26 urinary bladder urothelial carcinoma specimens, showing significantly increase corresponding to advanced primary stage (p = 0.003 and p < 0.001, respectively). An immunohistochemistry analysis and H-score calculation were performed to determine DDR2 expression in 340 urinary tract urothelial carcinoma and 295 urinary bladder urothelial carcinoma. Assessments of the correlation to clinicopathologic features, disease-specific survival, and metastasis-free survival were conducted. The transcript levels in advanced stage were higher than those in early stage and were correlated with poor prognosis. The higher expression was positively correlated to higher pT status (p < 0.001), higher histological grade (urinary tract, p = 0.041; urinary bladder, p < 0.001), greater vascular invasion (p < 0.001), and higher mitotic rate (urinary tract, p = 0.039; urinary bladder, p < 0.001). Higher expression also indicates significantly worse disease-specific survival and metastasis-free survival. In vitro study revealed knockdown of DDR2 resulted in a depletion of cellular viability, migratory, and invasive ability, supporting the oncogenic function of DDR2.

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Upregulation of discoidin domain receptor 2 in nasopharyngeal carcinoma

Abstract: DDR2 was differentially upregulated in NPC and modulated by EBV Zta protein. DDR2 may play a role in NPC invasion and serve as a diagnostic and therapeutic target.

Cited by 31 publications

References 33 publications

Overexpression of DDR2 contributes to cell invasion and migration in head and neck squamous cell carcinoma

Overexpression of DDR2 contributes to cell invasion and migration in head and neck squamous cell carcinoma

Antitumor activity of 7RH, a discoidin domain receptor 1 inhibitor, alone or in combination with dasatinib exhibits antitumor effects in nasopharyngeal carcinoma cells

DDR2 overexpression in urothelial carcinoma indicates an unfavorable prognosis: a large cohort study

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