CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

Abstract

The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. However, tumor-specific UPR transducers are largely unknown. In the present study, we identified CD147, a cancer biomarker, as an UPR inducer in hepatocellular carcinoma (HCC). The expression of the major UPR target, Bip, was found to be positively associated with CD147 in human hepatoma tissues. By phosphorylating FAK and Src, CD147-enhanced TFII-I tyrosine phosphorylation at Tyr248. CD147 also induced p-TFII-I nuclear localization and binding to the Bip promoter where endoplasmic reticulum (ER) stress response element 1 (ERSE1) ( À 82/ À 50) is the most efficient target of the three ERSEs, thus increasing transcription of Bip. Furthermore, by inducing UPR, CD147 inhibited HCC cell apoptosis and decreased cell Adriamycin chemosensitivity, thus decreasing the survival rate of hepatoma-bearing nude mice. Together, these results reveal pivotal roles for CD147 in modulating the UPR in HCC and raise the possibility that CD147 is a target that promotes HCC cell apoptosis and increases the sensitivity of tumors to anti-cancer drugs. Therefore, CD147 inhibition provides an opportunity to enhance the efficacy of existing agents and represents a novel target for HCC treatment. The uncontrolled growth and insufficient vascularization of a tumor mass lead to a stressed state in the tumor microenvironment, which includes low oxygen supply, nutrient deprivation and pH changes. Microenvironment stresses directly impinge on the luminal milieu of the endoplasmic reticulum (ER) and might be sufficiently severe to cause ER stress (ERS). 1 These ERS conditions activate a range of cellular stress response pathways, including the unfolded protein response (UPR). 2,3 UPR activation has profound consequences for tumor growth and resistance to radiotherapy and chemotherapy. [4][5][6] Therefore, the UPR might be responsible for the failure of some patients to respond to treatment and is associated with a poor prognosis. 7 Given the observation that UPR is correlated with certain types of aggressive tumors, drug resistance, recurrence and poor survival, 8-11 the inhibition of the UPR pathway may yield more efficient treatments for cancer.Although there is sufficient evidence to indicate that the UPR is generally activated in solid tumors, the UPR remains poorly characterized in cancers. The three major UPR transducers are inositol-requiring enzyme 1 (IRE1), pancreatic kinase-like ER kinase (PERK) and the UPR-specific transcription factor, activating transcription factor 6 (ATF6).These factors all sense the presence of unfolded proteins in the ER lumen and transduce signals to the nucleus that activate the transcription of UPR target genes, such as Bip (also called glucose-regulated protein 78). 12-14 The overexpression of Bip as a result of the three major transducers has been reported in malignant breast disease, colon cancer and gastric and esophageal adenocarcinomas. [15][16][17][18] It has also been...

17β-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts

“…It has been reported that TFII-I undergoes a Src kinase-dependent phosphorylation and nuclear localization in response to growth factor signaling. 35,42 It has also been reported that ERK1/2, which is a downstream target of Ras, regulates the activity of TFII-I by direct phosphorylation. ERK1/2 forms an in vivo complex with TFII-I and dominant-negative Ras abrogates this interaction.…”

“…35 Briefly, full-length TFII-I was PCR-amplified using an Advantage-GC Genomic PCR kit (Clontech, Palo Alto, CA, USA), and the primers (synthesized by the Shanghai Sangon) were designed as follows: forward primer, 5 0 -TTG GATCCCGCCCCCCCGCTTCCCCGCACGCGC-3 0 (BamHI) and reverse primer, 5 0 -GCTCTAGAAAACTATGCCGTCAC AG-3 0 (XbaI). The products were confirmed by sequencing (Shanghai Sangon, Shanghai, China) and then cloned into the pcDNA3.1 vector (Promega, Madison, WI, USA).…”

A single nucleotide polymorphism in the promoter region (rs10877887) of let-7 is associated with hepatocellular carcinoma in a Chinese population

“…So far, several studies have identified the important role played by various genetic factors in the progression of HCC (Villanueva et al, 2010;Tang et al, 2012;Marquardt et al, 2013).…”

Inhibition of mitogen-activated protein kinase signaling pathway sensitizes breast cancer cells to endoplasmic reticulum stress-induced apoptosis

“…GRP78 expression is primarily regulated at the transcriptional level, mediated by multiple copies of the ER stress response element within the GRP78 promoter region (28). We showed by RT-qPCR that GRP78 mRNA levels were decreased by inhibition of MEK/ERK in the presence or absence of TM, indicating that the MEK/ERK pathway may participate in regulation of GRP78 transcription.…”