Hypoxia increases KIAA1199/CEMIP expression and enhances cell migration in pancreatic cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Oba T
PROVIDER: S-EPMC8440617 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Hypoxic stress drives cancer progression by causing a transcriptional reprogramming. Recently, KIAA1199 was discovered to be a cell-migration inducing protein (renamed CEMIP) that is upregulated in human cancers. However, the mechanism of induction of CEMIP in cancer was hitherto unknown. Here we demonstrate that hypoxia induces CEMIP expression leading to enhanced cell migration. Immunohistochemistry of human colon cancer tissues revealed that CEMIP is upregulated in cancer cells located at the invasive front or in the submucosa. CEMIP localization inversely correlated with E-cadherin expression, which is characteristic of the epithelial-to-mesenchymal transition. Mechanistically, hypoxia-inducible-factor-2? (HIF-2?), but not HIF-1? binds directly to the hypoxia response element within the CEMIP promoter region resulting in increased CEMIP expression. Functional characterization reveals that CEMIP is a downstream effector of HIF-2?-mediated cell migration. Expression of CEMIP was demonstrated to negatively correlate with the expression of Jarid1A, a histone demethylase that removes methyl groups from H3K4me3 (an activation marker for transcription), resulting in altered gene repression. Low oxygen tension inhibits the function of Jarid1A, leading to increased presence of H3K4me3 within the CEMIP promoter. These results provide insight into the upregulation of CEMIP within cancer and can lead to novel treatment strategies targeting this cancer cell migration-promoting gene.
| S-EPMC4653038 | biostudies-literature
Project description:Chemotherapy and immunotherapy for pancreatic ductal adenocarcinoma (PDAC) have limited success for the intricated surrounding cancer microenvironment. Hypoxic microenvironment in PDAC causes the activation of multiple different molecules and signaling pathways compared with normoxia. We studied the roles of BNIP3 for the migration and proliferation of PDAC and Panc1 cells in vitro. In the present study, we found that BNIP3 expression was elevated and enhanced the migration and proliferation of CFPAC-1 and Panc1 cells under hypoxia. The upregulation of BNIP3 was important for the autophagic activation, while inhibition of autophagy with siRNA targeting Atg5 and Atg7 impaired the hypoxia-induced cell migration and proliferation. Additionally, blocking ERK1/2 mitogen-activated protein kinase (MAPK) signaling with PD98058 significantly down-regulated BNIP3 expression, autophagic activation, as well as the migration and proliferation of CFPAC-1 and Panc1 cells under hypoxia. Collectively, our results here uncover a hitherto unknown hypoxia-BNIP3-autophagy axis in modulating the migration and proliferation and provide a potential intriguing drug target for the therapy of PDAC. BNIP3; Autophagy; ERK1/2; Pancreatic ductal adenocarcinoma; Hypoxia.
| S-EPMC9614569 | biostudies-literature
Project description:Because tumors are characterized by hypoxic environments, we used a novel in vitro noninvasive magnetic resonance imaging assay to examine the influence of invasive MDA-MB-231 breast cancer cells on the invasion and migration of human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) under normoxic and hypoxic conditions. Nonmalignant immortalized MCF-12A human mammary epithelial cells instead of cancer cells or chambers with HMVEC-dLy alone were used as controls for comparison. HMVEC-dLy cells were labeled with a T(2) contrast agent (Feridex), and their invasion and migration through extracellular matrix under normoxic and hypoxic conditions were monitored using magnetic resonance imaging. A significant increase in the invasion and migration of HMVEC-dLy cells was detected in the presence of cancer cells, which further increased significantly under hypoxic conditions. HMVEC-dLy cells formed interconnecting strands extending toward the cancer cells under normoxic but not under hypoxic conditions. Following reoxygenation, these interconnecting strands, extending from HMVEC-dLy cells toward the cancer cells, were observed. These data demonstrate the importance of hypoxia in lymphatic endothelial cell invasion and migration through extracellular matrix in the presence of cancer cells.
| S-EPMC2288542 | biostudies-literature
Project description:CEMIP (for "Cell migration-inducing protein" also called KIAA1199 and Hybid for "Hyaluronan-binding protein") expression is increased in cancers and described as a regulator of cell survival, growth and invasion. In rheumatoid arthritis, CEMIP is referred to as an angiogenic marker and participates in hyaluronic acid degradation. In this study, CEMIP expression is investigated in healthy and osteoarthritis (OA) cartilage from human and mouse. Its role in OA physiopathology is deciphered, specifically in chondrocytes proliferation and dedifferentiation and in the extracellular matrix remodeling. To this end, CEMIP, ?SMA and types I and III collagen expressions were assessed in human OA and non-OA cartilage. CEMIP expression was also investigated in a mouse OA model. CEMIP expression was studied in vitro using a chondrocyte dedifferentiation model. High-throughput RNA sequencing was performed on chondrocytes after CEMIP silencing. Results showed that CEMIP was overexpressed in human and murine OA cartilage and along chondrocytes dedifferentiation. Most of genes deregulated in CEMIP-depleted cells were involved in cartilage turnover (e.g., collagens), mesenchymal transition and fibrosis. CEMIP regulated ?-catenin protein level. Moreover, CEMIP was essential for chondrocytes proliferation and promoted ?SMA expression, a fibrosis marker, and TGF? signaling towards the p-Smad2/3 (Alk5/PAI-1) pathway. Interestingly, CEMIP was induced by the pSmad1/5 (Alk1) pathway. ?SMA and type III collagen expressions were overexpressed in human OA cartilage and along chondrocytes dedifferentiation. Finally, CEMIP was co-expressed in situ with ?SMA in all OA cartilage layers. In conclusion, CEMIP was sharply overexpressed in human and mouse OA cartilage and along chondrocytes dedifferentiation. CEMIP-regulated transdifferentiation of chondrocytes into "chondro-myo-fibroblasts" expressing ?-SMA and type III collagen, two fibrosis markers. Moreover, these "chondro-myo-fibroblasts" were found in OA cartilage but not in healthy cartilage.
| S-EPMC6362103 | biostudies-literature
Project description:Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. We originally identified KIAA1199 (now officially called CEMIP) as a transcript highly induced in colon cancer: initially designating the transcript as Colon Cancer Secreted Protein 1. We molecularly characterized CEMIP expression both at the mRNA and protein level and found it is a secreted protein induced an average of 54-fold in colon cancer. Knockout of CEMIPreduced the ability of human colon cancer cells to form xenograft tumors in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. We find CEMIP mRNA overexpression correlates with poorer patient survival. In stage III only (n = 31) or in combined stage II plus stage III colon cancer cases (n = 73), 5-year overall survival was significantly better (p = 0.004 and p = 0.0003, respectively) among patients with low CEMIP expressing tumors than those with high CEMIP expressing tumors. These results demonstrate that CEMIP directly facilitates colon tumor growth, and high CEMIP expression correlates with poor outcome in stage III and in stages II+III combined cohorts. We present CEMIP as a candidate prognostic marker for colon cancer and a potential therapeutic target.
| S-EPMC4741547 | biostudies-literature
Project description:Factors mediating mobilization of osteoblastic stem and progenitor cells from their bone marrow niche to be recruited to bone formation sites during bone remodeling are poorly known. We have studied secreted factors present in the bone marrow microenvironment and identified KIAA1199 (also known as CEMIP, cell migration inducing hyaluronan binding protein) in human bone biopsies as highly expressed in osteoprogenitor reversal cells (Rv.C) recruited to the eroded surfaces (ES), which are the future bone formation sites. In vitro, KIAA1199 did not affect the proliferation of human osteoblastic stem cells (also known as human bone marrow skeletal or stromal stem cells, hMSCs); but it enhanced cell migration as determined by scratch assay and trans-well migration assay. KIAA1199 deficient hMSCs (KIAA1199down) exhibited significant changes in cell size, cell length, ratio of cell width to length and cell roundness, together with reduction of polymerization actin (F-actin) and changes in phos-CFL1 (cofflin1), phos-LIMK1 (LIM domain kinase 1) and DSTN (destrin), key factors regulating actin cytoskeletal dynamics and cell motility. Moreover, KIAA1199down hMSC exhibited impaired Wnt signaling in TCF-reporter assay and decreased expression of Wnt target genes and these effects were rescued by KIAA1199 treatment. Finally, KIAA1199 regulated the activation of P38 kinase and its associated changes in Wnt-signaling. Thus, KIAA1199 is a mobilizing factor that interacts with P38 and Wnt signaling, and induces changes in actin cytoskeleton, as a mechanism mediating recruitment of hMSC to bone formation sites.
| S-EPMC6372631 | biostudies-literature
Project description:Cell migration-inducing protein (CEMIP) and binding immunoglobulin protein (BiP) are upregulated in human cancers, where they drive cancer progression and metastasis. It has been shown that CEMIP resides in the endoplasmic reticulum (ER) where it interacts with BiP to induce cell migration, but the relationship between the two proteins was previously unknown. Here we show that CEMIP mediates activation of the BiP promoter and upregulates BiP transcript and protein levels in breast cancer cell lines. Moreover, CEMIP overexpression confers protective adaptations to cancer cells under hypoxic conditions, by decreasing apoptosis, activating autophagy, and increasing glucose uptake, to facilitate tumor growth. We demonstrate that BiP signals downstream of CEMIP, modulating cellular resistance to hypoxia. Reducing BiP in CEMIP-expressing cells sensitized cells to hypoxia treatment, decreased glucose uptake, and resulted in tumor regression in vivo. Our study provides insights into the link between CEMIP and BiP expression and the pro-survival role they play in hypoxia. Better understanding of the mechanisms behind cancer cell adaptations to harsh tumor environments could lead to development of improved cancer treatments.
| S-EPMC6611512 | biostudies-literature
Project description:Our previous study shows that cellular retinoic acid binding protein II (CRABP-II) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and pre-cancerous lesions, but not detected in normal pancreatic tissues. In this study, we show that deletion of CRABP-II in PDAC cells by CRISPR/Cas9 does not affect cancer cell proliferation, but decreases cell migration and invasion. Gene expression microarray analysis reveals that IL-8 is one of the top genes whose expression is down-regulated upon CRABP-II deletion, while expression of MMP-2 and MMP-14, two targets of IL-8 are also significantly down-regulated. Moreover, we found that CRABP-II is able to form a complex with HuR, which binds to the 3'UTR of IL-8 messenger RNA (mRNA) and enhances IL-8 mRNA stability. Ectopic expression of flag-CRABP-II in CRABP-II knockout cells is able to rescue the expression of IL-8, MMP-2/MMP-14 and recovers cell migration. Using the orthotopic xenograft model, we further demonstrate that CRABP-II deletion impairs tumor metastasis to nearby lymph nodes. Taken together, our results reveal a novel pathway linking CRABP-II expression to enhanced PDAC metastasis, and hence we propose CRABP-II may serve as a new PDAC therapeutic target.
| S-EPMC5581040 | biostudies-literature
Project description:Carbohydrate antigen (CA) 19-9 is the only diagnostic marker used in pancreatic cancer despite its limitations. Here, we aimed to identify the diagnostic role of CEMIP (also called KIAA1199) combined with CA 19-9 in patients with pancreatic cancer. A retrospective analysis of prospectively collected patient samples was performed to determine the benefit of diagnostic markers in the diagnosis of pancreatic cancer. We investigated CEMIP and CA 19-9 levels in 324 patients with pancreatic cancer and 49 normal controls using serum enzyme-linked immunosorbent assay. Median CA 19-9 and CEMIP levels were 410.5?U/ml (40.8-3342.5) and 0.67?ng/ml (0.40-1.08), respectively, in patients with pancreatic cancer. The AUROC for CA 19-9 and CEMIP were 0.847 (95% confidence interval [CI]: 0.806-0.888) and 0.760 (95% CI: 0.689-0.831), respectively. Combination of CA 19-9 with CEMIP showed markedly improved AUROC over CA 19-9 alone in pancreatic cancer diagnosis (0.94 vs. 0.89; P?<?0.0001). CEMIP showed a diagnostic yield of 86.1% (68/79) in CA 19-9 negative pancreatic cancer. Combined use with CEMIP showed significantly improved diagnostic value compared with CA 19-9 alone in pancreatic cancer. Especially, CEMIP may be a complementary marker in pancreatic cancer patients with normal CA 19-9 levels.
| S-EPMC5821821 | biostudies-other
Project description:Cutaneous hyaluronan (HA) is depolymerized to intermediate sizes in the extracellular matrix, and further fragmented in the regional lymph nodes. Previously, we showed that the HA-binding protein involved in HA depolymerization (HYBID), also known as KIAA1199/CEMIP, is responsible for the first step of HA depolymerization. Recently, mouse transmembrane 2 (mTMEM2) with high structural similarity to HYBID was proposed to be a membrane-bound hyaluronidase. However, we showed that the knockdown of human TMEM2 (hTMEM2) conversely promoted HA depolymerization in normal human dermal fibroblasts (NHDFs). Therefore, we examined the HA-degrading activity and function of hTMEM2 using HEK293T cells. We found that human HYBID and mTMEM2, but not hTMEM2, degraded extracellular HA, indicating that hTMEM2 does not function as a catalytic hyaluronidase. Analysis of the HA-degrading activity of chimeric TMEM2 in HEK293T cells suggested the importance of the mouse GG domain. Therefore, we focused on the amino acid residues that are conserved in active mouse and human HYBID and mTMEM2 but are substituted in hTMEM2. The HA-degrading activity of mTMEM2 was abolished when its His248 and Ala303 were simultaneously replaced by the corresponding residues of inactive hTMEM2 (Asn248 and Phe303). In NHDFs, enhancement of hTMEM2 expression by proinflammatory cytokines decreased HYBID expression and increased hyaluronan synthase 2-dependent HA production. The effects of proinflammatory cytokines were abrogated by hTMEM2 knockdown. A decreased HYBID expression by interleukin-1β and transforming growth factor-β was canceled by hTMEM2 knockdown. In conclusion, these results indicate that hTMEM2 is not a catalytic hyaluronidase, but a regulator of HA metabolism.
| S-EPMC10276149 | biostudies-literature