Cell-intrinsic PD-1 promotes proliferation in pancreatic cancer by targeting CYR61/CTGF via the hippo pathway

Pu, Ning; Gao, Shanshan; Yin, Hanlin; Li, Jian ang; Wu, Wen-Chuan; Fang, Yuan; Zhang, Lei; Rong, Yefei; Xu, Xuefeng; Wang, Dansong; Kuang, Tiantao; Jin, Dayong; Yu, Jun; Lou, Wenhui

doi:10.1016/j.canlet.2019.06.013

Cited by 75 publications

(88 citation statements)

References 45 publications

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“…It has been shown that MMP3 and CCN2 (aka connective tissue growth factor (CTGF)) are often increased in tumor-stroma tissues or patients' serum, and are thus biomarkers correlated with poor prognosis in cancer [18][19][20][21][22]. It has been also shown that MMP3 and CCN2/CTGF promote tumor progression through processes including rapid metastasis and tumor-stroma interactions [23][24][25][26]. CCN2/CTGF up-regulates MMP family proteins in cancer [27], while MMP3 regulates CCN2/CTGF by two mechanisms, including (i) intracellular MMP3, which directly activates the CCN2/CTGF gene to induce the production of CCN2/CTGF protein in chondrocytes [28,29] and (ii) MMPs, which cleave CCN2/CTGF to generate bioactive fragments essential for angiogenesis and osteoclastogenesis [30,31].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

Okusha

Eguchi

Tran

et al. 2020

Cancers

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Matrix metalloproteinase 3 (MMP3) plays multiple roles in extracellular proteolysis as well as intracellular transcription, prompting a new definition of moonlighting metalloproteinase (MMP), according to a definition of protein moonlighting (or gene sharing), a phenomenon by which a protein can perform more than one function. Indeed, connective tissue growth factor (CTGF, aka cellular communication network factor 2 (CCN2)) is transcriptionally induced as well as cleaved by MMP3. Moreover, several members of the MMP family have been found within tumor-derived extracellular vesicles (EVs). We here investigated the roles of MMP3-rich EVs in tumor progression, molecular transmission, and gene regulation. EVs derived from a rapidly metastatic cancer cell line (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich, LuM1-derived EVs were disseminated to multiple organs through body fluid and were pro-tumorigenic in an allograft mouse model, which prompted us to define LuM1-EVs as oncosomes in the present study. Oncosome-derived MMP3 was transferred into recipient cell nuclei and thereby trans-activated the CCN2/CTGF promoter, and induced CCN2/CTGF production in vitro. TRENDIC and other cis-elements in the CCN2/CTGF promoter were essential for the oncosomal responsivity. The CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects such as the inhibition of migration and invasion of tumor cells, and a reduction in CCN2/CTGF promoter activity and fragmentations in vitro. A high expression level of MMP3 or CCN2/CTGF mRNA was prognostic and unfavorable in particular types of cancers including head and neck, lung, pancreatic, cervical, stomach, and urothelial cancers. These data newly demonstrate that oncogenic EVs-derived MMP is a transmissive trans-activator for the cellular communication network gene and promotes tumorigenesis at distant sites.

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Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

Okusha

Eguchi

Tran

et al. 2020

Cancers

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“…Via regulating the protein levels and activity of YAP/TAZ, MOB1 acts as a tumor suppressor and loss of MOB1 promotes cell proliferation and induces cancers [4,6,[14][15][16]. In PDAC, it has been reported that intrinsic programmed cell death protein 1(PD-1) bound to MOB1 and inhibited MOB1's phosphorylation which increased the activation of YAP and promoted PDAC progression [17]. It has been reported that ubiquitin ligase praja2 ubiquitylated and degraded MOB1 and promoted glioblastoma growth [18].…”

Section: Introductionmentioning

confidence: 99%

Lysine demethylase 2 (KDM2B) regulates hippo pathway via MOB1 to promote pancreatic ductal adenocarcinoma (PDAC) progression

Quan

Chen

Jiao

et al. 2020

J Exp Clin Cancer Res

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Background: Mps1 binding protein (MOB1) is one of the core components of the mammalian Hippo pathway and plays important roles in cancer development. However, its expression, function and regulation in pancreatic ductal adenocarcinoma (PDAC) have not been revealed yet. Methods: The expression of MOB1 and lysine demethylase 2B (KDM2B) in PDAC and adjacent normal pancreas tissues were measured. Also, the underlying mechanisms of altered MOB1 expression and its impact on PDAC biology were investigated. Results: We revealed for the first time that MOB1 was decreased expression in PDAC and was a statistically significant independent predictor of poor survival, and restored expression of MOB1 suppressed the proliferation, migration and invasion of PDAC cells. Further studies demonstrated that KDM2B directly bound to the promoter region of MOB1, and suppressed the promoter activity of MOB1 and transcriptionally inhibited the MOB1 expression. Furthermore, KDM2B regulated Hippo pathway and promoted PDAC proliferation, migration and invasion via MOB1. Conclusion: This study demonstrated the mechanism and roles of a novel KDM2B/MOB1/Hippo signaling in PDAC progression.

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“…It was rstly reported that the expression of PD-1 was also presented in cancer cells and promoted the occurrence and development of tumors in melanoma [8]. Other studies have also shown that the expression of cell-intrinsic PD-1 promotes the development of liver cancer and pancreatic cancer, and the survival rate of patients with high expression is lower [41,42]. Tumor cell-intrinsic PD-1 promotes the occurrence of melanoma and hepatocellular carcinoma by activating the mTOR signaling [12].…”

Section: Discussionmentioning

confidence: 99%

“…Tumor cell-intrinsic PD-1 promotes the occurrence of melanoma and hepatocellular carcinoma by activating the mTOR signaling [12]. In pancreatic cancer, cell-intrinsic PD-1 promoted tumor growth through the Hippo signaling pathway outside the immune system [42]. However, Du et al found that cell-intrinsic PD-1 was presented in NSCLC as a tumor suppressor [43].…”

Section: Discussionmentioning

confidence: 99%

PD-L1 associated with the expression of cancer cell-intrinsic PD-1 and p-S6 proteins and predicted a good prognosis in nasopharyngeal carcinoma

Zhang

Zheng

Zhan

et al. 2020

Preprint

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Aims: programmed cell death ligand 1 (PD-L1) is the ligand of programmed death 1 (PD-1) which is a host immunity inhibitory receptor. PD-L1 expressed in tumor cells has been widely discussed, while there is little research about tumor intrinsic-PD-1. P-S6 is an important downstream effector of the PI3K/AKT/mTOR pathway. This study aimed to investigate the expression of PD-L1 protein and its relationship with cancer cell-intrinsic PD-1 protein and p-S6 in nasopharyngeal carcinoma (NPC). Methods: the expression of PD-L1, PD-1 and p-S6 proteins in tissues of NPC, non-cancerous nasopharyngeal epithelia, primary lesions and matching metastases was detected by immunohistochemistry. Results: PD-L1, PD-1 and p-S6 expression and co-expression of PD-L1 and PD-1 proteins were significantly higher in NPC than those of in the non-cancerous nasopharyngeal epithelia, respectively (all P<0.05). Furthermore, there was evidently elevated expression of PD-1 and co-expression of PD-L1 and PD-1 in matched metastasis of NPC compared to their primary lesions (all P<0.01). Overall survival rate for NPC patients with positive expression of PD-L1 (P =0.035) was significantly higher than others. Multivariate Cox proportional hazard regression analysis identified that positive expression of PD-L1 (P=0.002) and p-S6 (P=0.003) were independent prognostic factors for NPC patients. Conclusions: positive expression of PD-L1 associated with expression of cancer cell-intrinsic PD-1 and p-S6, PD-L1 might be a good prognostic biomarker and p-S6 could serve as a valuable independent poor prognostic biomarker for NPC patients.

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Cell-intrinsic PD-1 promotes proliferation in pancreatic cancer by targeting CYR61/CTGF via the hippo pathway

Cited by 75 publications

References 45 publications

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

Lysine demethylase 2 (KDM2B) regulates hippo pathway via MOB1 to promote pancreatic ductal adenocarcinoma (PDAC) progression

PD-L1 associated with the expression of cancer cell-intrinsic PD-1 and p-S6 proteins and predicted a good prognosis in nasopharyngeal carcinoma

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