Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

Nishida, Yoshihiro; Knudson, Warren; Knudson, Cheryl B.; Ishiguro, Naoki

doi:10.1016/j.yexcr.2005.03.026

Cited by 61 publications

(72 citation statements)

References 33 publications

(31 reference statements)

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“…Treatment of these cells with exogenous high-molecular weight HA showed a similar increase in cell motility. Exogenous HA was recently reported to stimulate osteosarcoma cell migration in support of our data (18). In the present study and in agreement with previous (18), downregulation of HAS2 expression by siRNA inhibited MG-63 cell ability to migrate.…”

Section: Discussionsupporting

confidence: 94%

“…Exogenous HA was recently reported to stimulate osteosarcoma cell migration in support of our data (18). In the present study and in agreement with previous (18), downregulation of HAS2 expression by siRNA inhibited MG-63 cell ability to migrate. The addition of PTH (1-34) to HAS2-defficient osteosarcoma cells did not stimulate their migration, suggesting that HAS2-synthesized HA participates in the PTH (1-34) effect.…”

Section: Discussionsupporting

confidence: 94%

“…PTH has been reported to strongly stimulate the HA production of both normal (15,16) and carcinogenic cells of the osteoblastic lineage (17). It has been previously demonstrated that the antisense inhibition of HAS2, via reduction of HA accumulation and cell-associated matrix formation (18), inhibits MG-63 osteosarcoma cell proliferation, motility, and invasiveness. In view of the fact that PTH-related pathways have been previously suggested to affect osteoblastic cell migration (19), we hypothesized that in osteosarcoma cell lines PTH peptides could modulate the expression of HA metabolism-related genes and, consequently, the migration capacity of these cells.…”

Section: Introductionmentioning

confidence: 99%

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Parathyroid hormone (PTH) peptides through the regulation of hyaluronan metabolism affect osteosarcoma cell migration

et al. 2010

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SummaryParathyroid hormone (PTH) strongly stimulates hyaluronan (HA) synthesis and secretion of both normal and carcinogenic cells of the osteoblastic lineage and improves skeletal microarchitecture. HA, a glycosaminoglycan component of the extracellular matrix (ECM), is capable of transmitting ECM-derived signals to regulate cellular function. In this study, we investigated whether the changes of HA metabolism induced by PTH (1-34) and PTH (7-84) peptides in moderately MG-63 and well-differentiated Saos 2 osteosarcoma cell lines, are correlated to their migration capabilities. Our results demonstrate that intermittent PTH (1-34) treatment significantly (P 0.01) supported the migration of MG-63 cells, increased their HA-synthase-2 (HAS2) expression (P 0.001), and enhanced their high-molecular size HA deposition in the pericellular matrix. Both increased endogenous HA production (P 0.01) and treatment with exogenous high-molecular weight HA (P 0.05) correlated to a significant increase of MG-63 cell migration capacity. Transfection with siHAS2 showed that PTH (1-34), mainly through HAS2, enhanced HA and regulated MG-63 cell motility. Interestingly, continuous PTH (1-34) treatment stimulated both Saos 2 cell HAS2 (P 0.001) and HAS1 (P 0.001) isoform expression inhibited their HYAL2 expression (P 0.001) and modestly (P 0.05) enhanced their migration. Therefore, the PTH (1-34) administration mode appears to distinctly modulate the migratory responses of the MG-63 moderately and Saos 2 well-differentiated osteosarcoma cell lines. Conclusively, the obtained data suggest that there is a regulatory effect of PTH (1-34), in an administration mode-dependent manner, on HA metabolism that is essential for osteosarcoma cell migration.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Parathyroid hormone (PTH) peptides through the regulation of hyaluronan metabolism affect osteosarcoma cell migration

et al. 2010

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“…Therefore, HAS2, which synthesizes an extremely large HA (average >2x10 6 Da), may play a crucial role in the formation of the pericellular coat. A recent study reported that formation of the pericellular coat, on osteosarcoma cell line MG63, was suppressed by treatment with HAS2 antisense oligonucleotides (47). This finding does not conflict with the findings of our study.…”

Section: Discussionsupporting

confidence: 79%

HAS3-related hyaluronan enhances biological activities necessary for metastasis of osteosarcoma cells

Tofuku

Yokouchi²,

Murayama³

et al. 2006

Int J Oncol

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Abstract. Several studies have suggested that increased production of hyaluronan (HA) is associated with metastatic behavior in various malignant tumors. To our knowledge, HA molecular weights required for metastasis are still unsolved in osteosarcoma. We examined the size of HA and hyaluronan synthase (HAS) isoforms related to biological functions required for metastasis in the LM8 stably highly metastatic osteosarcoma cell line. We found that HA of molecular weight which HAS3 produces enhanced biological functions related to metastasis such as cell proliferation, invasion, and degradation of extracellular matrix. Moreover, cell proliferation and invasion were inhibited by suppressing the activity of HAS3 expressed in LM8 cells, using hyaluronan synthase suppressor, 4-methylumbelliferone (MU). HA with the molecular weight related to HAS2 was the most adherent to CD44 in LM8 cells, suggesting that HAS2 may play an important role in pericellular coat formation. These results suggest that HAS3-related HA enhances crucial biological activities necessary for metastasis and that HAS2-related HA offers an advantageous environment for osteosarcoma cells.

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“…Knockdown of the HAS genes in tumor cells was reported to inhibit their proliferation, invasion and motility in vitro and tumor growth and metastasis in vivo (16)(17)(18)(19)(20)(21)(22). In particular, it has been reported that the levels of HAS2 expression are often correlated with malignant behavior in various cancer cells such as breast cancer, fibrosarcoma and osteosarcoma cells (17,(23)(24)(25). Furthermore, HAS2 is a key molecule for the induction of the epithelial-mesenchymal transition (EMT) with HA assembly (26)(27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

Fragmented hyaluronan is an autocrine chemokinetic motility factor supported by the HAS2-HYAL2/CD44 system on the plasma membrane

Saito

Kawana²,

Azuma³

et al. 2011

Int J Oncol

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Abstract. Hyaluronan (HA) is synthesized by HA synthase (HAS) 1, HAS2 and HAS3, and degraded by hyaluronidase (HYAL) 1 and HYAL2 in a CD44-dependent manner. HA and HYALs are intricately involved in tumor growth and metastasis. Random cell movement is generally described as chemokinesis, and represents an important step at the beginning of tumor cell liberation from the primary site. To investigate the roles of HAS2 and HYAL2/CD44 in cell motility, we examined HeLa-S3 cells showing spontaneous chemokinesis. HeLa-S3 cells expressed HAS2 and HAS3. siRNA-mediated knockdown of HAS2 decreased spontaneous chemokinesis of HeLa-S3 cells. Although HeLa-S3 cells secreted 50 ng/ml of high molecular weight (HMW)-HA (peak: 990 kDa) into the culture supernatant after 6 h of culture, exogenously added HMW-HA did not enhance spontaneous chemokinesis of the cells. These observations suggested that HeLa-S3 cells may have a self-degrading system for HA to regulate their spontaneous chemokinesis. To examine this possibility, we investigated the effects of siRNA-mediated knockdown of HYAL2 or CD44 on the spontaneous chemokinesis of HeLa-S3 cells. Knockdown of either molecule decreased the spontaneous chemokinesis of the cells. Low molecular weight (LMW)-HA (23 kDa) reversed the HYAL2 siRNA-mediated reduction in spontaneous chemokinesis of HeLa-S3 cells to the level in control cells stimulated with the same HA. These findings indicate that the HAS2-HYAL2/CD44 system may support spontaneous chemokinesis of human cancer cells through self-degradation of HMW-HA to produce LMW-HA by an autocrine mechanism. Consequently, our study may further expand our understanding of HA functions in cancer.

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Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

Cited by 61 publications

References 33 publications

Parathyroid hormone (PTH) peptides through the regulation of hyaluronan metabolism affect osteosarcoma cell migration

Parathyroid hormone (PTH) peptides through the regulation of hyaluronan metabolism affect osteosarcoma cell migration

HAS3-related hyaluronan enhances biological activities necessary for metastasis of osteosarcoma cells

Fragmented hyaluronan is an autocrine chemokinetic motility factor supported by the HAS2-HYAL2/CD44 system on the plasma membrane

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