Human Cancer Metastasis Research Articles

Peptide-functionalized metal-organic framework nanocomposite for ultrasensitive detection of secreted protein acidic and rich in cysteine with practical application

In this work, we have prepared peptide-functionalized metal-organic frameworks (MOFs) as signal-amplifying tags for the detection of secreted protein acidic and rich in cysteine (SPARC). Furthermore, enzyme-MOF nanocomposites are fabricated via a coprecipitation strategy between horse radish peroxidase (HRP) and ZIF-90, where ZIF-90 is used as a protective support for HRP immobilization. Meanwhile, the peptide sequence has been designed as SPARC-binding peptide, which imparts biorecognition functionality to HRP@ZIF-90 for performing a colorimetric sensor. Therefore, during the test, HRP molecules can be quickly released from nanocomposites by acidic condition to catalyze chromogenic reaction, enabling the ultrasensitive detection of SPARC with a low detection limit of 30 fg/mL. Moreover, the content of SPARC in colon cancer tissues with different degrees of differentiation can be determined with this sensor, demonstrating that the expression of SPARC is closely related to the occurrence, invasion and metastasis of human colon cancer. These results may show the potential applications of this biosensor in SPARC fundamental research as well as clinical diagnosis in the future.

Biological functions and clinical applications of exosomal long non-coding RNAs in cancer.

Exosomes are extracellular vesicles secreted by donor cells, and one of the important roles of exosomes is intercellular communication. Exosomes contain proteins, lipids, DNA and RNA. The components exert their functions by modulating the cellular processes of recipient cells. Exosomal long non‐coding RNAs (lncRNAs) are important components and play multiple roles in tumorigenesis and tumour development. In this review, we summarize the biological functions and clinical applications of exosomal lncRNAs in cancer. Exosomal lncRNAs regulate cell proliferation, metastasis, drug resistance and angiogenesis in human cancers. Since exosomal lncRNAs are associated with clinicopathological characteristics of cancer, these might be potentially useful biomarkers for diagnosis and prognosis of cancer. Exosomal lncRNAs participate in multiple processes of cancer progression, which makes them promising therapeutic targets for cancer treatment.

Identification of PLOD Family Genes as Novel Prognostic Biomarkers for Hepatocellular Carcinoma.

BackgroundHepatocellular carcinoma (HCC) is one of the most common malignancies with rising incidence and persistently high mortality. Previous researches have demonstrated that some PLOD family members are associated with tumor progression and metastasis in most human cancers. However, the prognostic and biological roles of PLODs in HCC remain largely unknown.MethodsONCOMINE, HPA, UALCAN, GEPIA, cBioPortal, GeneMANIA, NetworkAnalyst, Metascape, DAVID 6.8, and TIMER were used to determine the prognostic values and biological function of PLOD family members in HCC.ResultsThe mRNA and protein expression patterns of PLOD family members were noticeably upregulated in HCC compared to normal tissue. The high expression levels of PLOD1 and PLOD2 genes were significantly correlated with higher tumor grades in HCC patients. In addition, the high expression levels of PLOD1–3 were remarkably associated with poor overall survival in HCC patients, while high PLOD1 and PLOD3 expression were markedly associated with worse disease-free survival. In the co-expression gene analysis, 20 genes were primarily associated with the differentially expressed PLOD family members in HCC cases. Through functional enrichment analysis, the biological functions of PLODs in HCC were mainly involved in collagen fibril organization, lysine degradation, collagen biosynthesis, and modifying enzymes. Furthermore, the expression levels of PLOD1–3 were positively correlated with the activities of tumor-infiltrating immune cells, including macrophages, neutrophils, CD4+ T cells, and dendritic cells. Besides, the expression levels of PLOD2 and PLOD3 were positively correlated with the infiltrating levels of B cells.ConclusionThe findings of this study could provide novel insights into the identification of prognostic biomarkers for HCC patients.

An integrated analysis to predict micro-RNAs targeting both stemness and metastasis in human gastric cancer.

Cancer stem cells (CSCs), a subpopulation of tumor cells, assess the capacity of self-renewal, metastasis, and therapeutic resistance. Regulation of CSCs and their epithelial to mesenchymal transition (EMT) potential is one of the promising strategies to eliminate cancer or to inhibit metastasis. Micro-RNAs (miRNAs) as regulators of several cell properties, such as self-renewal, metastasis, and resistance to the drug, could be proper targets in cancer diagnosis and therapy. The aim of the present study is to select common miRNAs targeting both self-renewal and metastasis in gastric cancer. Stemness-related and EMT-related genes were selected by literature mining. The common miRNAs targeting genes were chosen using different databases and r programming language. The expression pattern of selected miRNAs and genes was evaluated in gastrospheres-as a gastric CSC model-and gastric tumor biopsies. Based on the integrated analysis, six miRNAs common to both stemness and metastasis were identified. miR-200c-3p and miR-520c-3p overexpressed in MKN-45 gastrospheres and grade III tumors. In AGS spheres, however, miR-520c-3p and miR-200c-3p upregulation and miR-34a-5p downregulation were similar to grade II tumors. Interestingly, miR-200c-3p and miR-520c-3p indicated a positive correlation with OCT4 and NOTCH1 expression in grade III tumors and MKN-45 spheres. Protein-protein network revealed that the EMT acquisition can be induced by stemness activation through intermediated core-regulatory genes, including CTNNB1, CTNND1, MAML1, KAT2A, and MAML3. The upregulation of mir-200c-3p and mir-520c-3p could effect on stemness and metastasis in gastric cancer as well as gastric CSCs. Therefore, they can be used as diagnosis and prognostic factors.

Three-Dimensional Interactions Analysis of the Anticancer Target c-Src Kinase with Its Inhibitors.

Src family kinases (SFKs) constitute the biggest family of non-receptor tyrosine kinases considered as therapeutic targets for cancer therapy. An aberrant expression and/or activation of the proto-oncogene c-Src kinase, which is the oldest and most studied member of the family, has long been demonstrated to play a major role in the development, growth, progression and metastasis of numerous human cancers, including colon, breast, gastric, pancreatic, lung and brain carcinomas. For these reasons, the pharmacological inhibition of c-Src activity represents an effective anticancer strategy and a few compounds targeting c-Src, together with other kinases, have been approved as drugs for cancer therapy, while others are currently undergoing preclinical studies. Nevertheless, the development of potent and selective inhibitors of c-Src aimed at properly exploiting this biological target for the treatment of cancer still represents a growing field of study. In this review, the co-crystal structures of c-Src kinase in complex with inhibitors discovered in the past two decades have been described, highlighting the key ligand–protein interactions necessary to obtain high potency and the features to be exploited for addressing selectivity and drug resistance issues, thus providing useful information for the design of new and potent c-Src kinase inhibitors.

Trends in Bone Metastasis Modeling.

Bone is one of the most common sites for cancer metastasis. Bone tissue is composed by different kinds of cells that coexist in a coordinated balance. Due to the complexity of bone, it is impossible to capture the intricate interactions between cells under either physiological or pathological conditions. Hence, a variety of in vivo and in vitro approaches have been developed. Various models of tumor–bone diseases are routinely used to provide valuable information on the relationship between metastatic cancer cells and the bone tissue. Ideally, when modeling the metastasis of human cancers to bone, models would replicate the intra-tumor heterogeneity, as well as the genetic and phenotypic changes that occur with human cancers; such models would be scalable and reproducible to allow high-throughput investigation. Despite the continuous progress, there is still a lack of solid, amenable, and affordable models that are able to fully recapitulate the biological processes happening in vivo, permitting a correct interpretation of results. In the last decades, researchers have demonstrated that three-dimensional (3D) methods could be an innovative approach that lies between bi-dimensional (2D) models and animal models. Scientific evidence supports that the tumor microenvironment can be better reproduced in a 3D system than a 2D cell culture, and the 3D systems can be scaled up for drug screening in the same way as the 2D systems thanks to the current technologies developed. However, 3D models cannot completely recapitulate the inter- and intra-tumor heterogeneity found in patients. In contrast, ex vivo cultures of fragments of bone preserve key cell–cell and cell–matrix interactions and allow the study of bone cells in their natural 3D environment. Moreover, ex vivo bone organ cultures could be a better model to resemble the human pathogenic metastasis condition and useful tools to predict in vivo response to therapies. The aim of our review is to provide an overview of the current trends in bone metastasis modeling. By showing the existing in vitro and ex vivo systems, we aspire to contribute to broaden the knowledge on bone metastasis models and make these tools more appealing for further translational studies.

The roles of post-translational modifications and coactivators of STAT6 signaling in tumor growth and progression.

Signal transducers and activators of transcription 6 (STAT6) arehighly expressed in various tumors and associated with tumorigenesis, immunosuppression, proliferation, metastasisand poor prognosis in human cancers. In response to IL-4/13, STAT6 is phosphorylated, dimerizesand triggers transcriptional regulation after recruitment of coactivators to transcriptosome, such as CBP/p300, SRC-1, PARP-14 and PSF. Post-translational modifications, including phosphorylation, ubiquitination, ADP-ribosylation and acetylation, have been explored for molecular mechanisms of STAT6 in tumor development and management. STAT6 has been developed as a specific biomarker for distinguishing and diagnosing tumor phenotypes, although it is observed to be frequently mutated in metastatic tumors. In this article, we focus mainly on the structural characteristics ofSTAT6 and its rolein tumor growth and progression.

Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell invasion and metastasis.

TMPRSS2 is an important membrane-anchored serine protease involved in human prostate cancer progression and metastasis. A serine protease physiologically often comes together with a cognate inhibitor for execution of proteolytically biologic function; however, TMPRSS2’s cognate inhibitor is still elusive. To identify the cognate inhibitor of TMPRSS2, in this study, we applied co-immunoprecipitation and LC/MS/MS analysis and isolated hepatocyte growth factor activator inhibitors (HAIs) to be potential inhibitor candidates for TMPRSS2. Moreover, the recombinant HAI-2 proteins exhibited a better inhibitory effect on TMPRSS2 proteolytic activity than HAI-1, and recombinant HAI-2 proteins had a high affinity to form a complex with TMPRSS2. The immunofluorescence images further showed that TMPRSS2 was co-localized to HAI-2. Both KD1 and KD2 domain of HAI-2 showed comparable inhibitory effects on TMPRSS2 proteolytic activity. In addition, HAI-2 overexpression could suppress the induction effect of TMPRSS2 on pro-HGF activation, extracellular matrix degradation and prostate cancer cell invasion. We further determined that the expression levels of TMPRSS2 were inversely correlated with HAI-2 levels during prostate cancer progression. In orthotopic xenograft animal model, TMPRSS2 overexpression promoted prostate cancer metastasis, and HAI-2 overexpression efficiently blocked TMPRSS2-induced metastasis. In summary, the results together indicate that HAI-2 can function as a cognate inhibitor for TMPRSS2 in human prostate cancer cells and may serve as a potential factor to suppress TMPRSS2-mediated malignancy.

Genistein Suppresses v-Src-Driven Proliferative Activity by Arresting the Cell-Cycle at G2/M through Increasing p21 Level in Src-Activated Human Gallbladder Carcinoma cells

Activated Src have been strongly implicated in the development, progression, and metastasis of many human cancers. Although soy isoflavones exhibit potential anticancer activity, effects of isoflavones on oncogenic activity of Src remains unknown. Using v-src-transfected human adenocarcinoma cells (HAG/src3-1), we investigated the functional role of Src in anti-proliferative activity of isoflavones including genistein, daidzein, glycitein and equol. The growth of HAG/neo3-5 vehicle control cells was inhibited potently by genistein and equol, but modestly by daidzein and glycitein. In contrast, Src activation conferred resistance to either daidzein, glycitein or equol, but rendered the cells more sensitive to genistein, compared to HAG/neo3-5 cells. Genistein significantly arrested HAG/src3-1 cells at G2/M, while neither daidzein, glycitein nor equol arrested the cells at any cell cycle phases. Apoptosis was not induced by either isoflavones. Genistein increased the expression levels of p53 and p21 with decreased phosphorylated p21, but did not affect the levels of major cyclin-CDK complexes. Taken together, genistein would be considered as the only isoflavone component that may potentially suppress Src-driven proliferative activity by arresting at G2/M induction through increasing the p21 levels, thus providing the mechanistic rationale for the potential use of genistein for the prevention of human cancers with activated Src.

Paxillin knockdown suppresses metastasis and epithelial‑mesenchymal transition in colorectal cancer via the ERK signalling pathway.

Paxillin (PXN) is a cytoplasmic protein that plays an important role in regulating focal adhesion, cytoskeletal rearrangements and cell motility. The present study aimed to investigate the role of PXN in the metastasis of human colorectal cancer (CRC) and its possible mechanisms. Immunohistochemical staining of tissues from 102 surgical CRC patients revealed that high PXN expression was positively correlated with tumour-node-metastasis (TNM) stage, lymph node metastasis, distant metastasis, and recurrence at distant sites after radical surgery. In 24 cases of stage IV CRC, PXN expression in liver metastasis was higher than that in the matched primary tumour. The knockdown of PXN inhibited the proliferation, migration and invasion potential of SW480 cells in vitro and in vivo. Transmission electron microscopy revealed the effect of PXN on ultrastructural characteristics, observed mainly in microvilli and desmosomes. The downregulation of PXN decreased the activation of extracellular regulated protein kinase (ERK) and suppressed the epithelial-mesenchymal transition (EMT) process. Following the downregulation of PXN, the addition of an ERK activator or inhibitor restored or further suppressed EMT, respectively, accompanied by corresponding changes in cell migration and invasion. Collectively, the present results confirmed the important role of PXN in CRC metastasis and revealed that PXN regulated EMT progression via the ERK signalling pathway. PXN may represent a future therapeutic strategy to prevent the EMT-associated progression and invasion of CRC.

MEIS-mediated suppression of human prostate cancer growth and metastasis through HOXB13-dependent regulation of proteoglycans.

The molecular roles of HOX transcriptional activity in human prostate epithelial cells remain unclear, impeding the implementation of new treatment strategies for cancer prevention and therapy. MEIS proteins are transcription factors that bind and direct HOX protein activity. MEIS proteins are putative tumor suppressors that are frequently silenced in aggressive forms of prostate cancer. Here we show that MEIS1 expression is sufficient to decrease proliferation and metastasis of prostate cancer cells in vitro and in vivo murine xenograft models. HOXB13 deletion demonstrates that the tumor-suppressive activity of MEIS1 is dependent on HOXB13. Integration of ChIP-seq and RNA-seq data revealed direct and HOXB13-dependent regulation of proteoglycans including decorin (DCN) as a mechanism of MEIS1-driven tumor suppression. These results define and underscore the importance of MEIS1-HOXB13 transcriptional regulation in suppressing prostate cancer progression and provide a mechanistic framework for the investigation of HOXB13 mutants and oncogenic cofactors when MEIS1/2 are silenced.

In vivomodeling of metastatic human high-grade serous ovarian cancer in mice.

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.

MicroRNA-214-3p targets the PLAGL2-MYH9 axis to suppress tumor proliferation and metastasis in human colorectal cancer.

Evidence has shown that microRNAs (miRNAs) participate in the progression of CRC. Previous studies have indicated that miR-214-3p is abnormally expressed in various malignant tumors. However, the biological function it plays in CRC and the potential mechanism are unclear. Here, we demonstrated that miR-214-3p was obviously downregulated in CRC. Moreover, we found a strong correlation between the miR-214-3p level and tumor size and lymphatic metastasis. Furthermore, when miR-214-3p was decreased by an Lv-miR-214-3p inhibitor, the proliferation and migration of SW480 and HCT116 cells were significantly increased. As expected, the ability of proliferation and migration was significantly suppressed when miR-214-3p was overexpressed in DLD1 cells. According to the dual-luciferase reporter results, PLAGL2 was found to be a direct downstream molecule of miR-214-3p. Chromatin immunoprecipitation (CHIP) confirmed that MYH9, a well-known cytoskeleton molecule in CRC, was a direct targeting gene of PLAGL2. Silencing PLAGL2 or MYH9 could reverse the effect of a miR-214-3p inhibitor on CRC cells. In summary, our studies proved that low expression of miR-214-3p and overexpression of downstream PLAGL2 in CRC indicated a poor prognosis. MiR-214-3p suppressed the malignant behaviors of colorectal cancer by regulating the PLAGL2/MYH9 axis. MiR-214-3p might be a novel therapeutic target or prognostic marker for CRC.

Downregulation of HMGA1 Mediates Autophagy and Inhibits Migration and Invasion in Bladder Cancer via miRNA-221/TP53INP1/p-ERK Axis.

MicroRNAs (miRNAs) have been implicated in regulating the development and metastasis of human cancers. MiR-221 is reported to be an oncogene in multiple cancers, including bladder cancer (BC). Deregulation of autophagy is associated with multiple human malignant cancers. Whether and how miR-221 regulates autophagy and how miR-221 has been regulated in BC are poorly understood. This study explored the potential functions and mechanisms of miR-221 in the autophagy and tumorigenesis of BC. We showed that the downregulation of miR-221 induces autophagy via increasing TP53INP1 (tumor protein p53 inducible nuclear protein 1) and inhibits migration and invasion of BC cells through suppressing activation of extracellular signal-regulated kinase (ERK). Furthermore, the expression of miR-221 is regulated by high-mobility group AT-hook 1 (HMGA1) which is overexpressed in BC. And both miR-221 and HMGA1 are correlated with poor patient survival in BC. Finally, the downregulation of HMGA1 suppressed the proliferative, migrative, and invasive property of BC by inducing toxic autophagy via miR-221/TP53INP1/p-ERK axis. Collectively, our findings demonstrate that the downregulation of miR-221 and HMGA1 mediates autophagy in BC, and both of them are valuable therapeutic targets for BC.

Bcl6 Preserves the Suppressive Function of Regulatory T Cells During Tumorigenesis.

During tumorigenesis, tumor infiltrating regulatory T (Treg) cells restrict the function of effector T cells in tumor microenvironment and thereby promoting tumor growth. The anti-tumor activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of various types of human cancers. However, the immune suppressive function of Treg cells remains a major hurdle to broader effectiveness of tumor immunotherapy. In this article, we reported that the deletion of Bcl6 specifically in Treg cells led to stunted tumor growth, which was caused by impaired Treg cell responses. Notably, Bcl6 is essential in maintaining the lineage stability of Treg cells in tumor microenvironment. Meanwhile, we found that the absence of follicular regulatory T (Tfr) cells, which is a result of Bcl6 deletion in Foxp3+ cells, was dispensable for tumor control. Importantly, the increased Bcl6 expression in Treg cells is associated with poor prognosis of human colorectal cancer and lymph node metastasis of skin melanoma. Furthermore, Bcl6 deletion in Treg cells exhibits synergistic effects with immune checkpoint blockade therapy. Collectively, these results indicate that Bcl6 actively participates in regulating Treg cell immune responses during tumorigenesis and can be exploited as a therapeutic target of anti-tumor immunity.

Downregulation of MicroRNA-551b Correlates With Dissemination of Human Oral Squamous Cell Carcinoma

Altered expression of microRNAs contributes to invasion and metastasis of many human cancers; however, the importance of microRNAs in head and neck cancers remains to be elucidated. In this study, we examined whether altered microRNA (miR)-551b expression correlated with invasive phenotypes of human oral squamous cell carcinoma (OSCC) invivo and invitro. Real-time polymerase chain reaction was used to detect the expression level of miR-551b in 71 OSCC tissues with lymph node metastasis and 50 nonmetastatic OSCC tissues. We also constructed miR-551b mimic-transfected cell lines HN4 and HN12. The effects of overexpressing miR-551b on the proliferation, migration, and invasion of OSCC cells were examined using Cell Counting Kit 8 (Dojindo, Kumamoto, Japan), plate clone formation, wound healing, and Transwell invasion experiments (Corning, Corning, NY).The association between clinical pathologic parameters and the expression level of miR-551b was analyzed using Kaplan-Meier survival analysis. The expression of miR-551b measured 0.33±0.11 in the 71 OSCC tissues with lymph node metastasis versus 0.54±0.06 in the 50 tissues with non-lymph node metastasis (P=.021).Regarding OSCC patients, the expression of miR-551b negatively correlated with patients' overall survival (P=.035). The ectopic expression of miR-551b inhibited the invasion and migration of OSCC cells. This is the first report showing that reduced miR-551b expression may be an event leading to OSCC invasion and metastasis.

RAGE acts as an oncogenic role and promotes the metastasis of human lung cancer

RAGE (receptor for advanced glycation end-product) is thought to be associated with metastasis and poor prognosis of various types of cancer. However, RAGE is constitutively expressed in the normal lung and down-regulated in cancerous lung, while the opposite evidence shows that RAGE-mediated signaling contributes to the tumorigenesis of lung cancer. Therefore, the role of RAGE in lung cancer progression is still unclear to be further investigated. In this study, RAGE-overexpressed stable clones of human lung cancer A549 cells and two local lung adenocarcinoma cell lines CL1-0 and CL1-5 were utilized to verify the effect of RAGE on lung cancer cells while the in vivo xenograft animal model was further performed to evaluate the role of RAGE in the progression of lung cancer. The growth of A549 cells was inhibited by RAGE overexpression. p53-dependent p21CIP1 expression contributed to RAGE-induced growth inhibition by suppressing CDK2 kinase activity and retinoblastoma protein (RB) phosphorylation in vitro. On the other hand, RAGE overexpression promoted migration, invasion, and mesenchymal features of lung adenocarcinoma cells through ERK signaling. Furthermore, an in vivo xenograft experiment indicated that RAGE promoted the metastasis of lung cancer cells with p21CIP1 up-regulation, ERK activation, and the changes of EMT markers. Regarding to the involvement of tumor-associated macrophage (TAM) in the microenvironment, we monitored the expressions of TAM markers including CD68 and CD163 as well as angiogenesis marker CD31 in xenograft slice. The data showed that RAGE might induce the accumulation of TAM in lung cancer cells and further accelerate the in vivo tumor growth. In summary, our study provides evidence indicating the distinct in vitro and in vivo effects of RAGE and related mechanisms on tumor growth and metastasis, which shed light on the oncogenic role of RAGE in lung cancer.

Circulating Micro RNA 181A as Biomarker in Breast Cancer, Its Possible Association with Metastasis & Epithelial Mesenchymal Transformation

Background: Recent studies have reported the involvement of micro RNA 181a in diverse cellular functions. Though some studies have shown that miR-181a expression is downregulated in several human solid tumors, others have demonstrated that upregulation of miR-181a may promote metastasis and invasion of human cancers. Aim of the Study: The aim of this work is to detect the level of circulating miRNA-181a in breast cancer cases at different stages and to study its role in metastasis & epithelial mesenchymal transformation (EMT) through the possible association between miRNA 181a and transforming growth factor beta (TGFβ) signaling pathway. Subjects and Methods: The present work included 70 female patients, with breast cancer at different stages 30 patients with metastatic disease and 40 patients with non-metastatic disease 20 healthy subjects were taken as a control group. We detected miRNA-181a expression in peripheral blood with qRT PCR, and TGF-beta, SMAD-4, SNAIL-1 and Bim expression by quantitative PCR. Results: miRNA-181a, TGF-beta, SNAIL-1 and SMAD-4 were significantly upregulated in patients with metastatic breast cancer compared to patients with non-metastatic disease while Bim is significantly downregulated in metastatic versus non-metastatic group. Also, miRNA-181a was a prognostic marker for disease progression and overall survival. Conclusion: signaling pathway of TGFβ-SMAD, regulate miRNA-181a which in turn play role in stabilizing SNAIL transcription factor that promote tumor aggressiveness and metastasis through epithelial mesenchymal transition, as well as down-regulation of Bim.

MP01-06 EXOSOME-TRANSMITTED LONG NON-CODING RNA PLAT1 RECRUITS HNRNPA1 TO PROMOTE LYMPHATIC METASTASIS OF BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I (MP01)1 Apr 2020MP01-06 EXOSOME-TRANSMITTED LONG NON-CODING RNA PLAT1 RECRUITS HNRNPA1 TO PROMOTE LYMPHATIC METASTASIS OF BLADDER CANCER Changhao Chen*, Tianxin Lin, and Jian Huang Changhao Chen*Changhao Chen* More articles by this author , Tianxin LinTianxin Lin More articles by this author , and Jian HuangJian Huang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000815.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Bladder cancer is one of the most common genitourinary malignancy and the eighth leading cause of cancer-related death among males. LN metastasis confers to a poor prognosis of bladder cancer patients. Recent studies show that exosomal long non-coding RNAs (lncRNAs) are essential to the metastasis of human cancers. However, the underlying mechanisms of exosomal lncRNAs in LN metastasis of bladder cancer have not yet been elucidated. METHODS: RNA-sequencing identified the differentially expressed lncRNAs in urinary exosomes from bladder cancer patients and healthy controls. In vitro and in vivo experiments were used to evaluate the functional role of exosomal PLAT1. Pull-down and RIP assays were used to confirm the binding partner of PLAT1. ChIRP assays were utilized to examine the interaction of PLAT1 and IκBα promoter. ChIP assays assessed the H3K27e3 level in IκBα promoter. RESULTS: PLAT1 was identified as a exosomal lncRNA which was overexpressed in bladder cancer-secreted exosomes and correlated with the LN metastasis of bladder cancer. Overexpression of exosomal PLAT1 induced the lymphangiogenesis of bladder cancer in vitro. Consistently, exosomal PLAT1 overexpression facilitated LN metastasis of bladder cancer in popliteal LN metastasis model. Moreover, PLAT1 interacted with hnRNPA1, which further sorted PLAT1 into exosomes. PLAT1 encapsulated with exosomes was transmitted into human lymphatic endothelial cells (HLECs) and downregulated IκBα expression by recruiting hnRNPA1 to the promoter region of PROX1 and increasing H3K27me3 level. Furthermore, IκBα downregulation-mediated NF-κB signaling activation activated the expression of PROX1 and VEGF-C, which led to the lymphangiogenesis and LN metastasis of bladder cancer. CONCLUSIONS: Identification of exosomal PLAT1 for inducing lymphangiogenesis and lymphatic metastasis not only increases our knowledge of the biological basis for LN metastasis regulation but also develops a potential therapeutic target for LN metastasis in bladder cancer. Source of Funding: This study was supported by grants from the National Natural Science Foundation of China (Grant No. 81802530, 81672395, 81702951, 81672395, 81672807, 81702417, 81000917, 81402213, and 81370059), the Guangdong Science and Technology Department (Grant No. 2018A030313564, S2012010008934, 2014A030313044, 2014A030311047, 2016A030313340, 2016A030313296, and 2017A030313880). © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e3-e4 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Changhao Chen* More articles by this author Tianxin Lin More articles by this author Jian Huang More articles by this author Expand All Advertisement PDF downloadLoading ...

Bacterial type III effector protein HopQ inhibits melanoma motility through autophagic degradation of vimentin

Malignant melanoma is a fatal disease that rapidly spreads to the whole body. Treatments have limited efficiency owing to drug resistance and various side effects. Pseudomonas syringae pv. tomato (Pto) is a model bacterial pathogen capable of systemic infection in plants. Pto injects the effector protein HopQ into the plant cytosol via a type III secretion machinery and suppresses the host immunity. Intriguingly, host plant proteins regulated by HopQ are conserved even in humans and conferred in tumor metastasis. Nevertheless, the potential for HopQ to regulate human cancer metastasis was unknown. In this study, we addressed the suitability of HopQ as a possible drug against melanoma metastasis. In melanoma cells, overexpressed HopQ is phosphorylated and bound to 14-3-3 through its N-terminal domain, resulting in stronger interaction between HopQ and vimentin. The binding of HopQ to vimentin allowed for degradation of vimentin via p62-dependent selective autophagy. Attenuation of vimentin expression by HopQ inhibited melanoma motility and in vivo metastasis. These findings demonstrated that HopQ directly degraded vimentin in melanoma cells and could be applied to an inhibitor of melanoma metastasis.