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

Abstract

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.

ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells

“…In a recent report of DLBCL patients (n = 137) high ROR1 expression was significantly associated with B symptoms and Ann Arbor stage. The overall survival correlated significantly with ROR1 expression, B symptoms and LDH level, but only LDH was there an independent factor [25]. Collectively, data from most previous publications and the preliminary observations from the present study suggest that the expression of ROR1 may be related to poor prognosis and disease aggressiveness in DLBCL, a finding which is in line with reports in a variety of other malignancies.…”

“…ROR1 is expressed in B cell malignancies including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL) and recently also diffuse large B cell lymphoma (DLBCL) as well as in solid tumors such as lung, pancreatic, ovarian, and breast cancers [6,7,10,11,18,19,23]. siRNA transfection of tumor cells of both hematological and epithelial origin induced significant tumor cell death [10,18,24,25]. In several tumors, high expression of ROR1 correlated with short survival [10,25] or disease progression [26].…”

“…siRNA transfection of tumor cells of both hematological and epithelial origin induced significant tumor cell death [10,18,24,25]. In several tumors, high expression of ROR1 correlated with short survival [10,25] or disease progression [26].…”

A novel molecular classification of diffuse large B cell lymphoma based on Metabolism-related genes

“…Targeting ROR1 may provide a promising strategy for the treatment of DLBCL. [30] In rare cases, patients with relapsed and refractory DLBCL have achieved complete response, which suggests that some B-lymphomas may be extremely sensitive to rapalogs, possibly because they show active mTORC1 signal transduction [27].focal adhesion signal inhibitor E7123 and targeted ROR1 may be therapeutic strategies for nmftype2, but may not be effective for nmftype1. When PI3K and Akt inhibitors were used in cell lines and mouse models, the phosphatidylinositol-3-kinase (PI3K)α/δ(PI3Kα/δ) Inhibitor AZD8835 showed signi cant effect in ABC DLBCL model, while azd5363, a protein kinase B (Akt) inhibitor AZD5363 induced apoptosis in PTEN de cient DLBCLs.…”

The clinicopathological and prognostic characteristics of mucinous micropapillary carcinoma of the breast

“…Antigen retrieval was performed with citrate buffer and microwave heat induction. IHC analysis was conducted as previously described [10,11]. All antibodies used for IHC assay were listed in Table 1.…”