Dataset Information

Nuclear translocation of pro-amphiregulin induces chemoresistance in gastric cancer.

ABSTRACT: Amphiregulin (AR) is derived from a membrane-anchored form (proAR) by ectodomain shedding, and is a ligand that activates epidermal growth factor receptor (EGFR). We have recently shown that proAR translocates from the plasma membrane to the nucleus after truncation of 11 amino acids at the C-terminus, which is independent of the conventional EGFR signaling pathway. Although proAR immunoreactivity has reportedly been detected in the nucleus of cancer cells, its biological meaning has never been investigated. This study was performed to investigate the roles of proAR nuclear translocation in human gastric cancer. We constructed proAR truncated 11 amino acids at the C-terminus (proAR?C11) that spontaneously translocates to the nucleus, and established proAR?C11-expression regulatable gastric cancer cells (MKN45, MKN28) using the tet-off system. Using these cells, we found that proAR nuclear translocation significantly induced chemoresistance in vitro and in vivo. Analyzing the relationship between immunoreactive localization of proAR and the clinical outcome for 46 advanced gastric cancer cases treated with chemotherapy, median survival time was 311 days in 16 patients with AR-positive staining in the nucleus and 387 days in 30 patients with AR-negative staining (P < 0.05). The present study demonstrates that proAR nuclear translocation increases resistance to anti-cancer drugs, which might be associated with poor prognosis in human gastric cancer.

SUBMITTER: Yoshida M

PROVIDER: S-EPMC7659380 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Nuclear translocation of pro-amphiregulin induces chemoresistance in gastric cancer.

Yoshida Michihiro M Shimura Takaya T Fukuda Shinji S Mizoshita Tsutomu T Tanida Satoshi S Kataoka Hiromi H Kamiya Takeshi T Nakazawa Takahiro T Higashiyama Shigeki S Joh Takashi T

Cancer science 20120220 4

Amphiregulin (AR) is derived from a membrane-anchored form (proAR) by ectodomain shedding, and is a ligand that activates epidermal growth factor receptor (EGFR). We have recently shown that proAR translocates from the plasma membrane to the nucleus after truncation of 11 amino acids at the C-terminus, which is independent of the conventional EGFR signaling pathway. Although proAR immunoreactivity has reportedly been detected in the nucleus of cancer cells, its biological meaning has never been ...[more]

PMID: 22320154

Similar Datasets

Project description:BackgroundMembrane-anchored heparin-binding epidermal growth factor-like growth factor (proHB-EGF) yields soluble HB-EGF, which is an epidermal growth factor receptor (EGFR) ligand, and a carboxy-terminal fragment of HB-EGF (HB-EGF-CTF) after ectodomain shedding. We previously reported that HB-EGF-CTF and unshed proHB-EGF which has the cytoplasmic domain of proHB-EGF (HB-EGF-C), translocate from the plasma membrane to the nucleus and regulate cell cycle after shedding stimuli. However, the significance of nuclear exported HB-EGF-C in human gastric cancer is unclear.MethodsWe investigated the relationship between intracellular localization of HB-EGF-C and clinical outcome in 96 gastric cancer patients treated with gastrectomy. Moreover, we established stable gastric cancer cell lines overexpressing wild-type HB-EGF (wt-HB-EGF) and mutated HB-EGF (HB-EGF-mC), which prevented HB-EGF-C nuclear translocation after shedding. Cell motility between these 2 gastric cancer cell lines was investigated using a transwell invasion assay and a wound healing assay.ResultsOf the 96 gastric cancer cases, HB-EGF-C immunoreactivity was detected in both the nucleus and cytoplasm in 19 cases (19.8 %) and in the cytoplasm only in 25 cases (26.0 %). The nuclear immunoreactivity of HB-EGF-C was significantly increased in stage pT3/4 tumors compared with pT1/2 tumors (T1/2 vs. T3/4: 11.1 % vs. 36.4 %, P < 0.01). The growth of wt-HB-EGF- and HB-EGF-mC-expressing cells significantly increased compared with control cells, but the growth of HB-EGF-mC-expressing cells was significantly decreased compared with wt-HB-EGF-expressing cells. Gastric cancer cell invasion obviously increased in wt-HB-EGF-expressing cells, but invasion in HB-EGF-mC-expressing cells showed a slight increase compared with control cells. Moreover, wt-HB-EGF overexpression increased the effectiveness of wound healing, but had no significant effect in HB-EGF-mC-expressing cells.ConclusionsBoth the function of HB-EGF as an EGFR ligand and a novel signal for HB-EGF-C nuclear translocation induce gastric cancer growth, whereas HB-EGF-C nuclear translocation independently plays a critical role in gastric cancer invasion. The present study demonstrated that HB-EGF-C nuclear translocation might be crucial in gastric cancer invasion. HB-EGF-C nuclear translocation may offer a prognostic marker and a new molecular target for gastric cancer therapy.

Project description:Chemotherapy is currently the main treatment for unresectable or advanced postoperative gastric cancers. However, its efficacy is negatively affected by the occurrence of chemoresistance, which severely affects patient prognosis. Recently, dysregulation in autophagy has been suggested as a potential mechanism for chemoresistence, and long noncoding RNA (lncRNA) also shows its regulatory role in cancer drug resistance. Using RNA sequencing, we found that lncRNA EIF3J-DT was highly expressed in drug-resistant gastric cancer cells. In-vitro and in-vivo experiments showed that EIF3J-DT activated autophagy and induced drug resistance in gastric cancer cells by targeting ATG14. Bioinformatics and experimental results showed that EIF3J-DT regulated the expression of ATG14 through direct binding to enhance stabilization of ATG14 mRNA and via blocking the degradation of ATG14 mRNA through competitively binding with microRNA (miRNA) MIR188-3p. Therefore, EIF3J-DT increased the expression of ATG14, contributing to activation of autophagy and chemoresistance. Furthermore, it was confirmed that EIF3J-DT and ATG14 were highly expressed in gastric cancer patients resistant to chemotherapy, and this was closely associated with patient prognosis. In conclusion, EIF3J-DT is involved in the regulation of autophagy and chemoresistance in gastric cancer cells by targeting ATG14. It may be a suitable new target for enhancing chemosensitivity and improving prognosis.Abbreviations: 3-MA: 3-methyladenine; 5-Fu: 5-fluorouracil; ATG: autophagy related; C-CASP3: cleaved caspase 3; C-CASP7: cleaved caspase 7; C-PARP: cleaved PARP; CQ: chloroquine; CR: complete response; DIG: digoxigenin; ESR1: estrogen receptor 1; FBS: fetal bovine serum; FISH: fluorescence in situ hybridization; IHC: immunohistochemistry; ISH: in situ hybridization; lncRNA: long noncoding RNA; miRNA: microRNA; MUT: mutant; NC: negative control; OXA: oxaliplatin; PBS: phosphate-buffered saline; PD: progressive disease; PFA: paraformaldehyde; PR: partial response; qPCR: quantitative polymerase chain reaction; RAPA: rapamycin; SD: stable disease; TEM: transmission electron microscopy; WT: wild type.

Dataset Information

Nuclear translocation of pro-amphiregulin induces chemoresistance in gastric cancer.

Publications

Nuclear translocation of pro-amphiregulin induces chemoresistance in gastric cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets