Silencing of Receptor Tyrosine Kinase ROR1 Inhibits Tumor-Cell Proliferation via PI3K/AKT/mTOR Signaling Pathway in Lung Adenocarcinoma

Yan-chun, Liu; Yang, Hui; Chen, Tianxing; Luo, Yongbin; Xu, Zhengfu; Li, Ying; Yang, Jiahui

doi:10.1371/journal.pone.0127092

Cited by 52 publications

(51 citation statements)

References 53 publications

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“…Two experienced pathologists without any knowledge of the clinicopathological information independently evaluated the result of the immunoreactivity. A semi-quantitatively scoring system (0–3) was used to evaluate the expression level of ROR1 as described previously22. The intensity of the staining was classified as negative, weak, moderate or strong.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, higher level of ROR1 is associated with more aggressiveness and poor prognosis in breast cancer and ovarian cancer, where ROR1 regulates expression of the genes involved in epithelial-mesenchymal transition (EMT)2021. In lung cancer cell lines, ROR1 sustains a favorable balance between pro-survival PI3K-AKT and pro-apoptotic p38 signaling, and knockdown of ROR1 induces apoptosis in cancer cells22. Wnt5a, a ligand of ROR1, induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation23.…”

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confidence: 99%

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ROR1 is a novel prognostic biomarker in patients with lung adenocarcinoma

Zheng

Zhou

et al. 2016

Sci Rep

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Currently, there is no reliable biomarker to clinically predict the prognosis of lung adenocarcinoma (ADC). The receptor-tyrosine-kinase like orphan receptor 1 (ROR1) is reported to be overexpressed and associated with poor prognosis in several tumors. This study aimed to examine the expression of ROR1 and evaluate its prognostic significance in human lung ADC patients. In this present study, Western blot analysis and immunohistochemistry were performed to characterize expression of ROR1 protein in lung ADC patients. The results revealed that ROR1 protein expression was significantly higher in lung ADC tissues than that in their adjacent non-tumor tissues. Patients at advanced stages and those with positive lymph node metastasis expressed higher level of ROR1 (P < 0.001). Moreover, Chi-square test showed that ROR1 expression was correlated to gender (P = 0.028), the 7th edition of the American Joint Committee on Cancer tumor-node-metastasis (AJCC TNM) staging system and lymph node metastasis (P < 0.001). Kaplan-Meier survival analysis indicated an association of high ROR1 expression with worse overall survival (OS) in lung ADC patients (P < 0.001). Multivariate COX regression analysis further confirmed that ROR1 is an independent prognostic predictor (P < 0.001, HR = 4.114, 95% CI: 2.513–6.375) for OS. Therefore, ROR1 expression significantly correlates with malignant attributes of lung ADC and it may serve as a novel prognostic marker in lung ADC patients.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

ROR1 is a novel prognostic biomarker in patients with lung adenocarcinoma

Zheng

Zhou

et al. 2016

Sci Rep

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“…The receptor tyrosine kinase ROR1 serves as a Wnt5a receptor and is widely expressed in embryonic development and multiple human cancers (1–11). There are three described splice variants of Ror1 : variant 1 (v1; UniProt IDQ01973-1) encodes a transmembrane protein consisting of 934 amino acids (aa) expressed on the cell surface; intracellular variant 2 (v2; UniProt IDQ01973-2) lacks the amino-terminal 549 aa of ROR1; and intracellular/secreted variant 3 (v3; UniProt IDQ01973-3) putatively encodes the amino-terminal 393 aa (12, 13).…”

Section: Introductionmentioning

confidence: 99%

“…Multiple groups have demonstrated protein and cell-surface expression of ROR1 in B-CLL, mantle cell lymphoma (MCL), and a subset of B-cell ALL using flow cytometry (2, 5, 12, 18). Immunohistochemistry (IHC) of both frozen and formalin fixed paraffin embedded (FFPE) tumor samples using antibodies targeting the N-terminal region of ROR1, detected ROR1 in many solid tumors, however many studies described mainly cytoplasmic staining, not the expected cell-surface expression of Ror1-v1 (3, 4, 6, 7, 10, 11). ROR1 expression has also been characterized in normal human tissues by transcriptomics, immunoblot and IHC.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues

Balakrishnan

Goodpaster

Randolph‐Habecker

et al. 2017

Clinical Cancer Research

159

136

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Purpose This study examines cell-surface ROR1 expression in human tumors and normal tissues. ROR1 is considered a promising target for cancer therapy due to putative tumor-specific expression and multiple groups are developing antibodies and/or chimeric antigen receptor-modified T cells to target ROR1. On-target, off-tumor toxicity is a challenge for most non-mutated tumor antigens, however prior studies suggest that ROR1 is absent on most normal tissues. Experimental Design Our studies show that published antibodies lack sensitivity to detect endogenous levels of cell-surface ROR1 by immunohistochemistry (IHC) in FFPE tissues. We developed a ROR1-specific monoclonal antibody (mAb) targeting the carboxy-terminus of ROR1, and evaluated its specificity and sensitivity in IHC. Results The 6D4 mAb is a sensitive and specific reagent to detect cell-surface ROR1 by IHC. The data shows that ROR1 is homogenously expressed on a subset of ovarian cancer, triple negative breast cancer and lung adenocarcinomas. Contrary to previous findings, we found ROR1 is expressed on several normal tissues including parathyroid, pancreatic islets and regions of the esophagus, stomach and duodenum. The 6D4 mAb recognizes rhesus ROR1, and ROR1 expression was similar in human and macaque tissues suggesting that the macaque is a suitable model to evaluate safety of ROR1 targeted therapies. Conclusions ROR1 is a promising immunotherapeutic target in many epithelial tumors, however high cell-surface ROR1 expression in multiple normal tissues raises concerns for on-target off-tumor toxicities. Clinical translation of ROR1 targeted therapies warrants careful monitoring of toxicities to normal organs, and may require strategies to ensure patient safety.

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ROR1 associates unfavorable prognosis and promotes lymphoma growth in DLBCL by affecting PI3K/Akt/mTOR signaling pathway

Yuan

Wang

et al. 2019

BioFactors

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The receptor-tyrosine-kinase (RTK)-like orphan receptor 1 (ROR1) is a transmembrane glycoprotein regarded as a tumor-associated antigen. ROR1 plays an important role in cancer development, but the detailed function of ROR1 in diffuse large B-cell lymphoma (DLBCL) remains unclear. In this study, we first detected ROR1 expression and evaluated the relationship between ROR1 expression and the clinicopathological characteristics of DLBCL patients. Next we employed shRNA-mediated knockdown of ROR1 in DLBCL cell line to explore the characteristics of ROR1 in DLBCL development both in vitro and in vivo. The results showed a significantly higher level of ROR1 in DLBCL tissues than in lymphatic hyperplasia tissues. High ROR1 expression was correlated with unfavorable prognosis in DLBCL patients. Furthermore, ROR1 knockdown inhibited the growth and BioFactors 416Research Communication induced the apoptosis in DLBCL cells and xenografts. In addition, shROR1 inhibited activation of the PI3K/Akt/mTOR signaling pathway, both in vitro and in vivo. Taken together, our results suggest that ROR1 is a novel prognostic marker for DLBCL survival and ROR1 significantly promotes DLBCL tumorigenesis by regulating the PI3K/Akt/mTOR signaling pathway. Targeting ROR1 may provide a promising strategy for DLBCL treatment.

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Silencing of Receptor Tyrosine Kinase ROR1 Inhibits Tumor-Cell Proliferation via PI3K/AKT/mTOR Signaling Pathway in Lung Adenocarcinoma

Cited by 52 publications

References 53 publications

ROR1 is a novel prognostic biomarker in patients with lung adenocarcinoma

ROR1 is a novel prognostic biomarker in patients with lung adenocarcinoma

Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues

ROR1 associates unfavorable prognosis and promotes lymphoma growth in DLBCL by affecting PI3K/Akt/mTOR signaling pathway

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