Hyaluronic acid fuels pancreatic cancer cell growth.
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ABSTRACT:
SUBMITTER: Kim PK
PROVIDER: S-EPMC8730721 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:OBJECTIVE:To study the correlation between hyaluronic acid (HA), hyaluronic acid synthase (HAS) and human renal clear cell carcinoma (RCCC). METHODS:The expression of three HAS isoforms' gene and HA in 93 RCCC tissues, 27 nephridial tissues by the side of RCCC from two hospitals were measured with Real-Time RT-PCR?Western Blot and immunohistochemical methods and analyzed. RESULTS:All RCCC and adjacent normal tissues expressed three HASs' mRNA & protein; at the mRNA level, both RCCC and adjacent normal tissues, expressed more HAS3 than HAS1 or HAS2, their differences were statistically significant (all P values <0.05); but, at the protein level, all HAS isoforms presented the equivalent expression. Compared with the adjacent non-neoplastic kidney tissues, the expression of all HAS isoforms' mRNA in RCCC tissues were increased evidently and their differences were significant (all P values <0.0001); but at the protein level, only the expression of HAS3 increased evidently (P=0.022). In all adjacent normal tissues, more than 80% renal tubular cells strongly expressed HA, however, only the minority RCCC cases (16/93) presented weakly positive HA staining in few cancer nests (5%-30%), the difference were significant (P<0.0001). In RCCC tissues subgrouped according to clinical stage, pathological grade, lymphatic metastasis or not and distant metastasis or not, the HASs' mRNA & protein differential expression all had no statistical significance (all P values >0.05). CONCLUSION:Different from other malignancy, HA and HASs (except for HAS3) may not play important roles in the biological progress of human RCCC.
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Project description:The prognosis of pancreatic cancer remains poor. Intraoperative fluorescence imaging of tumors could improve staging and surgical resection, thereby improving prognosis. However, imaging pancreatic cancer with macromolecular delivery systems, is often hampered by nonspecific organ accumulation. Methods: We describe the rational development of hyaluronic acid (HA) conjugates that vary in molecular weight and are conjugated to near infrared fluorescent (NIRF) dyes that have differences in hydrophilicity, serum protein binding affinity, and clearance mechanism. We systematically investigated the roles of each of these properties on tumor accumulation, relative biodistribution, and the impact of intraoperative imaging of orthotopic, syngeneic pancreatic cancer. Results: Each HA-NIRF conjugate displayed intrapancreatic tumor enhancement. Regardless of HA molecular weight, Cy7.5 conjugation directed biodistribution to the liver, spleen, and bowels. Conjugation of IRDye800 to 5 and 20 kDa HA resulted in low liver and spleen signal while enhancing the tumor up to 14-fold compared to healthy pancreas, while 100 kDa HA conjugated to IRDye800 resulting in liver and spleen accumulation. Conclusion: These studies demonstrate that by tuning HA molecular weight and the physicochemical properties of the conjugated moiety, in this case a NIRF probe, peritoneal biodistribution can be substantially altered to achieve optimized delivery to tumors intraoperative abdominal imaging.
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Project description:As a potential novel agent for treating pancreatic cancer, methylseleninic acid (MSeA) was evaluated in cell culture and xenograft models. Results showed that MSeA induced G1 cell cycle arrest and apoptosis in a majority of human and mouse pancreatic cancer cell lines, but G2 arrest in human PANC-1 and PANC-28 cell lines. In contrast to our previous finding in human prostate cancer LNCaP cells having a lack of P53 activation by MSeA, induction of G2 arrest in PANC-1 cells was accompanied by increased mutant P53 Ser15 phosphorylation, upregulation of P53-targets P21Cip1 and GADD45 and G2 checkpoint kinase (Chk2) activation, suggestive of DNA damage responses. A rapid inhibition of AKT phosphorylation was followed by reduced mTOR signaling and increased autophagy in PANC-1 cells attenuating caspase-mediated apoptosis execution. Furthermore, daily oral treatment with MSeA (3 mg Se/kg body weight) significantly suppressed growth of subcutaneously inoculated PANC-1 xenograft in SCID mice. Immunohistochemical analyses detected increased p-Ser15 P53, P21Cip1, pS139-H2AX (DNA damage responses), and caspase-3 cleavage and decreased pSer473AKT and Ki67 proliferative index and reduced intratumor vascular density in MSeA-treated xenograft. These results provide impetus for further research of MSeA in the therapy and/or chemoprevention of pancreatic cancer.
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Project description:Receptor for hyaluronic acid (HA)-mediated motility (RHAMM) expression is upregulated in pancreatic ductal adenocarcinoma (PDAC). In the present study, small interfering RNA knockdown was used to investigate the regulatory mechanism and function of RHAMM in PDAC cells. Reverse transcription-quantitative PCR was used to measure the mRNA expression levels of RHAMM, hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1, HYAL2 and HYAL3) in eight PDAC cell lines. Cell migration was assessed using a Transwell assay, while HA concentration was measured using an ELISA. The results revealed that RHAMM-knockdown significantly increased migration in two PDAC cell lines, significantly decreased migration in one cell line and did not affect migration in the other cell lines, and was positively associated with changes in HA production. There was a linear negative correlation between RHAMM mRNA expression and HA concentration in PDAC cells and tissues. The negative correlation between RHAMM mRNA expression and HA concentration was demonstrated in other models, including SUIT2 cells treated with an HA inhibitor or stimulator and a system involving co-culture of SUIT2 cells and stromal fibroblasts. The present findings demonstrated a negative correlation between RHAMM mRNA expression and HA production in a subset of PDAC cell lines. The efficacy of a therapeutic strategy targeting RHAMM should be carefully evaluated in future studies.
| S-EPMC7491089 | biostudies-literature
Project description:In this paper, we designed a quantitative model of biological membranes by the deposition of planar lipid membranes on solid substrates (called supported membranes), and immobilized biotinylated oligomers of hyaluronic acid (oligo-HA, 6-8 disaccharide units in length) to the membrane surface via neutravidin cross-linkers. By controlling the self-assembly of biotinylated lipid anchors, the mean distance between the oligo-HA molecules on the membrane could be controlled to nm accuracy. The adhesion and motility of pancreatic adenocarcinoma cells expressing different splice variants of the HA-binding cell surface receptor CD44 on these surfaces were investigated quantitatively. The combination of label-free, time-lapse imaging of living cells and statistical analysis suggests that the static morphology (global shape and cytoskeleton remodeling) of cells, their stochastic morphological dynamics, and the probability of directed motion reflect the metastatic behaviour of the cancer cells.
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Project description:The oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation was reported to be the signature genetic event in most cases of pancreatic ductal adenocarcinoma (PDAC). Hepassocin (HPS/FGL1) is involved in regulating lipid metabolism and the progression of several cancer types; however, the underlying mechanism of HPS/FGL1 in the KRAS mutant PDAC cells undergoing eicosapentaenoic acid (EPA) treatment remains unclear. We measured HPS/FGL1 protein expressions in a human pancreatic ductal epithelial (HPNE) normal pancreas cell line, a KRAS-wild-type PDAC cell line (BxPC-3), and KRAS-mutant PDAC cell lines (PANC-1, MIA PaCa-2, and SUIT-2) by Western blot methods. HEK293T cells were transiently transfected with corresponding KRAS-expressing plasmids to examine the level of HPS expression with KRAS activation. We knocked-down HPS/FGL1 using lentiviral vectors in SUIT-2 cells and measured the cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenicity assays. Furthermore, a lipidomic analysis was performed to profile changes in lipid metabolism after HPS/FGL1 knockdown. We found that the HPS/FGL1 level was significantly upregulated in KRAS-mutated PDAC cells and was involved in KRAS/phosphorylated (p)-signal transduction and activator of transcription 3 (STAT3) signaling, and the knockdown of HPS/FGL1 in SUIT-2 cells decreased cell proliferation through increasing G2/M cell cycle arrest and cyclin B1 expression. In addition, the knockdown of HPS/FGL1 in SUIT-2 cells significantly increased omega-3 polyunsaturated fatty acids (PUFAs) and EPA production but not docosahexaenoic acid (DHA). Moreover, EPA treatment in SUIT-2 cells reduced the expression of de novo lipogenic protein, acetyl coenzyme A carboxylase (ACC)-1, and decreased p-STAT3 and HPS/FGL1 expressions, resulting in the suppression of cell viability. Results of this study indicate that HPS is highly expressed by KRAS-mutated PDAC cells, and HPS/FGL1 plays a crucial role in altering lipid metabolism and increasing cell growth in pancreatic cancer. EPA supplements could potentially inhibit or reduce ACC-1-involved lipogenesis and HPS/FGL1-mediated cell survival in KRAS-mutated pancreatic cancer cells.
| S-EPMC8001293 | biostudies-literature
Project description:The methylation status of a promoter influences gene expression and aberrant methylation during tumor development has important functional consequences for pancreatic and other cancers. Using methylated CpG island amplification and promoter microarrays, we identified ANK1 as hypomethylated in pancreatic cancers. Expression analysis determined ANK1 as commonly overexpressed in pancreatic cancers relative to normal pancreas. ANK1 was co-expressed with miR-486 in pancreatic cancer cells. Stable knockdown of ANK1 in the pancreatic cancer cell line AsPC1 led to changes in cell morphology, and decreases in colony formation. Stable knockdown of ANK1 also marked reduced the growth of tumors in athymic nude mice. Among patients undergoing pancreaticoduodenectomy, those with pancreatic cancers expressing ANK1 had a poorer prognosis than those without ANK1 expression. These findings indicate a role for ANK1 overexpression in mediating pancreatic cancer tumorigenicity.
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Project description:Hyaluronic acid, a nonsulfated, linear glycosaminoglycan, is ubiquitously distributed in the extracellular matrix and is known to facilitate tumor progression by enhancing invasion, growth, and angiogenesis. Native HA has been attached to substrates to create patterned surfaces resistant to cell adhesion, and has been utilized in a variety of cell adhesion studies using either non covalently bound layers patterned by soft lithography or related methods. We use a new approach to study cell interactions with HA-presenting regions, by covalently linking HA adjacent to PEG-ylated regions, which resist cell adhesion. Colon and breast cancer cells seeded on the patterned HA surfaces adhere preferentially on HA-presenting regions and proliferate there. Furthermore, we demonstrate that cell adhesion is inhibited with the blocking of HA receptor, CD44, and that cellular adhesive processes, through protrusions spreading onto the HA surface, enhance spreading and movement outside the HA-presenting regions. Overall, this approach allows high-resolution analysis of cancer cell attachment, growth, and migration on exogenous native HA.
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Project description:Three-dimensional (3D) tissue culture models may recapitulate aspects of the tumorigenic microenvironment in vivo, enabling the study of cancer progression in vitro. Both hypoxia and matrix stiffness are known to regulate tumor growth. Using a modular culture system employing an acrylated hyaluronic acid (AHA) hydrogel, three hydrogel matrices with distinctive degrees of viscoelasticity - soft (78±16 Pa), medium (309± 57 Pa), and stiff (596± 73 Pa) - were generated using the same concentration of adhesion ligands. Oxygen levels within the hydrogel in atmospheric (21 %), hypoxic (5 %), and severely hypoxic (1 %) conditions were assessed with a mathematical model. HT1080 fibrosarcoma cells, encapsulated within the AHA hydrogels in high densities, generated nonuniform oxygen distributions, while lower cell densities resulted in more uniform oxygen distributions in the atmospheric and hypoxic environments. When we examined how varying viscoelasticity in atmospheric and hypoxic environments affects cell cycles and the expression of BNIP3 and BNIP3L (autophagy and apoptosis genes), and GLUT-1 (a glucose transport gene), we observed that HT1080 cells in 3D hydrogel adapted better to hypoxic conditions than those in a Petri dish, with no obvious correlation to matrix viscoelasticity, by recovering rapidly from possible autophagy/apoptotic events and alternating metabolism mechanisms. Further, we examined how HT1080 cells cultured in varying viscoelasticity and oxygen tension conditions affected endothelial sprouting and invasion. We observed that increased matrix stiffness reduced endothelial sprouting and invasion in atmospheric conditions; however, we observed increased endothelial sprouting and invasion under hypoxia at all levels of matrix stiffness with the upregulation of vascular endothelial growth factor (VEGF) and angiopoeitin-1 (ANG-1). Overall, HT1080 cells encapsulated in the AHA hydrogels under hypoxic stress recovered better from apoptosis and demonstrated greater angiogenic induction. Thus, we propose that oxygen tension more profoundly influences cell fate and the angiogenic potential of 3D cultured HT1080 fibrosarcoma cells than does matrix stiffness.
| S-EPMC3987918 | biostudies-literature
Project description:The mechanisms by which Streptococcus pneumoniae obtains carbohydrates for growth during airway colonization remain to be elucidated. The low concentration of free carbohydrates in the normal human airway suggests that pneumococci must utilize complex glycan structures for growth. The glycosaminoglycan hyaluronic acid is present on the apical surface of airway epithelial cells. As pneumococci express a hyaluronate lyase (Hyl) that cleaves hyaluronic acid into disaccharides, we hypothesized that during colonization pneumococci utilize the released carbohydrates for growth. Hyaluronic acid supported significant pneumococcal growth in an hyl-dependent manner. A phosphoenolpyruvate-dependent phosphotransferase system (PTS) and an unsaturated glucuronyl hydrolase (Ugl) encoded downstream of hyl are also essential for growth on hyaluronic acid. This genomic arrangement is present in several other organisms, suggesting conservation of the utilization mechanism between species. In vivo experiments support the hypothesis that S. pneumoniae utilizes hyaluronic acid as a carbon source during colonization. We also demonstrate that pneumococci can utilize the hyaluronic acid capsule of other bacterial species for growth, suggesting an alternative carbohydrate source for pneumococcal growth. Together, these data support a novel function for pneumococcal degradation of hyaluronic acid in vivo and provide mechanistic details of growth on this glycosaminoglycan.
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