Hyaluronan stimulates pancreatic cancer cell motility

Cheng, Xinqi; Kohi, Shiro; Koga, Atsuhiro; Hirata, Keiji; Sato, Norihiro

doi:10.18632/oncotarget.6617

Cited by 62 publications

(54 citation statements)

References 41 publications

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“…We also showed that direct addition of LMW‐HA (25–75 kDa) to cultured PDAC cells increased their migration more robustly than HMW‐HA (400–600 kDa) (Fig. ) . Thus, the effects of HA on cell behavior may depend on its size and cell type; however, the mechanism underlying these different effects of HA is not clearly understood.…”

Section: Role Of Ha In Initiation and Progression Of Human Cancersmentioning

confidence: 88%

Role of hyaluronan in pancreatic cancer biology and therapy: Once again in the spotlight

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) remains the most deadly disease worldwide, with the lowest survival rate among all cancer types. Recent evidence suggests that hyaluronan (HA), a major component of ECM, provides a favorable microenvironment for cancer progression. Pancreatic ductal adenocarcinoma is typically characterized by a dense desmoplastic stroma containing a large amount of HA. Accumulation of HA promotes tumor growth in mice and correlates with poor prognosis in patients with PDAC. Because HA is involved in various malignant behaviors of cancer (such as increased cell proliferation, migration, invasion, angiogenesis, and chemoresistance), inhibiting HA synthesis/signaling or depleting HA in tumor stroma could represent a promising therapeutic strategy against PDAC. In this review article, we summarize our current understanding of the role of HA in the progression of PDAC and discuss possible therapeutic approaches targeting HA.

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Section: Role Of Ha In Initiation and Progression Of Human Cancersmentioning

confidence: 88%

Role of hyaluronan in pancreatic cancer biology and therapy: Once again in the spotlight

et al. 2016

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“…In particular, LMW-HA, rather than HMW-HA, is more likely to promote cancer growth and metastasis [8]. We also demonstrated that direct addition of LMW-HA to cultured PDAC cells increased their migration more robustly than HMW-HA [9]. Because HA is degraded by HYALs, accelerated HYAL activity is associated with aggressive tumor progression [3].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, low-molecular-weight- (LMW-) HA or small HA fragments, rather than HMW-HA, have been suggested to be essential for cancer progression in terms of invasion and metastasis [8]. We also reported LMW-HA stimulated PDAC cell migration [9]. Accumulating evidence suggests that HYAL has a critical role in tumor progression.…”

Section: Introductionmentioning

confidence: 86%

Hyaluromycin, a Novel Hyaluronidase Inhibitor, Attenuates Pancreatic Cancer Cell Migration and Proliferation

Kohi

Sato

Koga

et al. 2016

Journal of Oncology

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by accelerated production and degradation of hyaluronan (HA), a major component of extracellular matrix involved in the malignant phenotype of cancer. In particular, increased hyaluronidase (HYAL) activity plays a critical role in cancer progression, at least in part, by producing low-molecular-weight- (LMW-) HA or small fragments of HA, suggesting HYAL as a target for cancer treatment. Hyaluromycin, a new member of the rubromycin family of antibiotics, was isolated from the culture extract of a marine-derived Streptomyces hyaluromycini as a HYAL inhibitor. We investigated the antitumor effects of hyaluromycin in PDAC cells. We examined the effects of hyaluromycin on the proliferation and migration of PDAC cells. To elucidate the mechanisms underlying the effect of hyaluromycin on PDAC cells, we examined the concentration of LMW-HA in the conditioned media after treating PDAC cells with hyaluromycin. We demonstrate that hyaluromycin inhibits proliferation and migration of PDAC cells. We also found that these antitumor effects of hyaluromycin were associated with a decreased concentration of LMW-HA and a decreased phosphorylation of ribosomal protein S6. Our results suggest that hyaluromycin is a promising new drug against this highly aggressive neoplasm.

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“…Interestingly, low-molecular-weight HA (LMW-HA) or small HA fragments, rather than high-molecular-weight HA (HMW-HA), has been suggested to be essential for cancer progression in terms of invasion and metastasis [9, 10]. We also show that LMW-HA stimulates motility of PDAC cells [11]. HA, a large linear glycosaminoglycan of up to 10 6 -10 7 Da in its naïve form, is produced by HA-synthesizing enzymes (HASs) and degraded into smaller fragments by hyaluronidases (HYALs).…”

Section: Introductionmentioning

confidence: 90%

KIAA1199 is induced by inflammation and enhances malignant phenotype in pancreatic cancer

et al. 2017

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BackgroundRecent evidence suggests a critical role of hyaluronan (HA), especially low-molecular-weight HA (LMW-HA), in the aggressive tumor phenotype. Increased expression of KIAA1199, a newly identified protein involved in HA degradation, has been reported in various cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the functional significance of KIAA1199 in PDAC.MethodsUsing siRNA knockdown and forced expression models, we investigated the effects of KIAA1199 expression on malignant behaviors (proliferation, migration, and invasion) of PDAC cells. We also examined the effect of inflammation on the transcriptional regulation of KIAA1199 using a pro-inflammatory cytokine and anti-inflammatory agent.ResultsKnockdown of KIAA1199 expression using siRNA resulted in decreased cell migration and proliferation. On the other hand, forced expression of KIAA1199 using gene transduction significantly enhanced the migration and invasion. Importantly, increased KIAA1199 expression was associated with an increased level of LMW-HA in the conditioned medium. Exposure to a pro-inflammatory cytokine, interleukin-1ß, increased the KIAA1199 transcription and enhanced the migration. In contrast, treatment with NS-398, a cyclooxygenase-2 inhibitor, decreased the KIAA1199 expression and inhibited the migration.ConclusionsThese findings suggest that increased KIAA1199 expression may contribute to the aggressive phenotype partly through increasing the LMW-HA concentration. Our present results also suggest a possible link between inflammation, induced KIAA1199 expression, and enhanced migration during PDAC progression.

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Hyaluronan stimulates pancreatic cancer cell motility

Cited by 62 publications

References 41 publications

Role of hyaluronan in pancreatic cancer biology and therapy: Once again in the spotlight

Role of hyaluronan in pancreatic cancer biology and therapy: Once again in the spotlight

Hyaluromycin, a Novel Hyaluronidase Inhibitor, Attenuates Pancreatic Cancer Cell Migration and Proliferation

KIAA1199 is induced by inflammation and enhances malignant phenotype in pancreatic cancer

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