HYAL1-v1, an alternatively spliced variant of HYAL1 hyaluronidase

A negative regulator of bladder cancer

Vinata B. Lokeshwar, Veronica Estrella, Luis Lopez, Mario Kramer, Pablo Gomez, Mark S. Soloway, Bal L. Lokeshwar

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Tumor cells express HYAL1 hyaluronidase, which degrades hyaluronic acid. HYAL1 expression in bladder cancer cells promotes tumor growth, invasion, and angiogenesis. We previously described five alternatively spliced variants of HYAL1 that encode enzymatically inactive proteins. The HYAL1-v1 variant lacks a 30-amino acid sequence that is present in HYAL1. In this study, we examined whether HYAL1-v1 expression affects bladder cancer growth and invasion by stably transfecting HT1376 bladder cancer cells with a HYAL1-v1 cDNA construct. Although HYAL1-v1 transfectants expressed equivalent levels of enzymatically active HYAL1 protein when compared with vector transfectants, their conditioned medium had 4-fold less hyaluronidase activity due to a noncovalent complex formed between HYAL1 and HYAL1-v1 proteins. HYAL1-v1 transfectants grew 3- to 4-fold slower due to cell cycle arrest in the G2-M phase and increased apoptosis. In HYAL1-v1 transfectants, cyclin B1, cdc2/p34, and cdc25c levels were ≥2-fold lower than those in vector transfectants. The increased apoptosis in HYAL1-v1 transfectants was due to the extrinsic pathway involving Fas and Fas-associated death domain up-regulation, caspase-8 activation, and BID cleavage, leading to caspase-9 and caspase-3 activation and poly(ADP-ribose) polymerase cleavage. When implanted in athymic mice, HYAL1-v1-expressing tumors grew 3- to 4-fold slower and tumor weights at day 35 were 3- to 6-fold less than the vector tumors (P < 0.001). Whereas vector tumors were infiltrating and had high mitoses and microvessel density, HYAL1-v1 tumors were necrotic, infiltrated with neutrophils, and showed low mitoses and microvessel density. Therefore, HYAL-v1 expression may negatively regulate bladder tumor growth, infiltration, and angiogenesis.

Original languageEnglish
Pages (from-to)11219-11227
Number of pages9
JournalCancer Research
Volume66
Issue number23
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

Fingerprint

Hyaluronoglucosaminidase
Urinary Bladder Neoplasms
Neoplasms
Microvessels
Mitosis
Growth
Apoptosis
Cyclin B1
Proteins
Poly(ADP-ribose) Polymerases
Caspase 9
Caspase 8
G2 Phase
Hyaluronic Acid
Conditioned Culture Medium
Cell Cycle Checkpoints
Tumor Burden
Nude Mice
Caspase 3
Cell Division

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lokeshwar, V. B., Estrella, V., Lopez, L., Kramer, M., Gomez, P., Soloway, M. S., & Lokeshwar, B. L. (2006). HYAL1-v1, an alternatively spliced variant of HYAL1 hyaluronidase: A negative regulator of bladder cancer. Cancer Research, 66(23), 11219-11227. https://doi.org/10.1158/0008-5472.CAN-06-1121

HYAL1-v1, an alternatively spliced variant of HYAL1 hyaluronidase : A negative regulator of bladder cancer. / Lokeshwar, Vinata B.; Estrella, Veronica; Lopez, Luis; Kramer, Mario; Gomez, Pablo; Soloway, Mark S.; Lokeshwar, Bal L.

In: Cancer Research, Vol. 66, No. 23, 01.12.2006, p. 11219-11227.

Research output: Contribution to journalArticle

Lokeshwar, VB, Estrella, V, Lopez, L, Kramer, M, Gomez, P, Soloway, MS & Lokeshwar, BL 2006, 'HYAL1-v1, an alternatively spliced variant of HYAL1 hyaluronidase: A negative regulator of bladder cancer', Cancer Research, vol. 66, no. 23, pp. 11219-11227. https://doi.org/10.1158/0008-5472.CAN-06-1121
Lokeshwar, Vinata B. ; Estrella, Veronica ; Lopez, Luis ; Kramer, Mario ; Gomez, Pablo ; Soloway, Mark S. ; Lokeshwar, Bal L. / HYAL1-v1, an alternatively spliced variant of HYAL1 hyaluronidase : A negative regulator of bladder cancer. In: Cancer Research. 2006 ; Vol. 66, No. 23. pp. 11219-11227.
@article{746711c3b3b54d40bbe6c18aed99de0d,
title = "HYAL1-v1, an alternatively spliced variant of HYAL1 hyaluronidase: A negative regulator of bladder cancer",
abstract = "Tumor cells express HYAL1 hyaluronidase, which degrades hyaluronic acid. HYAL1 expression in bladder cancer cells promotes tumor growth, invasion, and angiogenesis. We previously described five alternatively spliced variants of HYAL1 that encode enzymatically inactive proteins. The HYAL1-v1 variant lacks a 30-amino acid sequence that is present in HYAL1. In this study, we examined whether HYAL1-v1 expression affects bladder cancer growth and invasion by stably transfecting HT1376 bladder cancer cells with a HYAL1-v1 cDNA construct. Although HYAL1-v1 transfectants expressed equivalent levels of enzymatically active HYAL1 protein when compared with vector transfectants, their conditioned medium had 4-fold less hyaluronidase activity due to a noncovalent complex formed between HYAL1 and HYAL1-v1 proteins. HYAL1-v1 transfectants grew 3- to 4-fold slower due to cell cycle arrest in the G2-M phase and increased apoptosis. In HYAL1-v1 transfectants, cyclin B1, cdc2/p34, and cdc25c levels were ≥2-fold lower than those in vector transfectants. The increased apoptosis in HYAL1-v1 transfectants was due to the extrinsic pathway involving Fas and Fas-associated death domain up-regulation, caspase-8 activation, and BID cleavage, leading to caspase-9 and caspase-3 activation and poly(ADP-ribose) polymerase cleavage. When implanted in athymic mice, HYAL1-v1-expressing tumors grew 3- to 4-fold slower and tumor weights at day 35 were 3- to 6-fold less than the vector tumors (P < 0.001). Whereas vector tumors were infiltrating and had high mitoses and microvessel density, HYAL1-v1 tumors were necrotic, infiltrated with neutrophils, and showed low mitoses and microvessel density. Therefore, HYAL-v1 expression may negatively regulate bladder tumor growth, infiltration, and angiogenesis.",
author = "Lokeshwar, {Vinata B.} and Veronica Estrella and Luis Lopez and Mario Kramer and Pablo Gomez and Soloway, {Mark S.} and Lokeshwar, {Bal L.}",
year = "2006",
month = "12",
day = "1",
doi = "10.1158/0008-5472.CAN-06-1121",
language = "English",
volume = "66",
pages = "11219--11227",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "23",

}

TY - JOUR

T1 - HYAL1-v1, an alternatively spliced variant of HYAL1 hyaluronidase

T2 - A negative regulator of bladder cancer

AU - Lokeshwar, Vinata B.

AU - Estrella, Veronica

AU - Lopez, Luis

AU - Kramer, Mario

AU - Gomez, Pablo

AU - Soloway, Mark S.

AU - Lokeshwar, Bal L.

PY - 2006/12/1

Y1 - 2006/12/1

N2 - Tumor cells express HYAL1 hyaluronidase, which degrades hyaluronic acid. HYAL1 expression in bladder cancer cells promotes tumor growth, invasion, and angiogenesis. We previously described five alternatively spliced variants of HYAL1 that encode enzymatically inactive proteins. The HYAL1-v1 variant lacks a 30-amino acid sequence that is present in HYAL1. In this study, we examined whether HYAL1-v1 expression affects bladder cancer growth and invasion by stably transfecting HT1376 bladder cancer cells with a HYAL1-v1 cDNA construct. Although HYAL1-v1 transfectants expressed equivalent levels of enzymatically active HYAL1 protein when compared with vector transfectants, their conditioned medium had 4-fold less hyaluronidase activity due to a noncovalent complex formed between HYAL1 and HYAL1-v1 proteins. HYAL1-v1 transfectants grew 3- to 4-fold slower due to cell cycle arrest in the G2-M phase and increased apoptosis. In HYAL1-v1 transfectants, cyclin B1, cdc2/p34, and cdc25c levels were ≥2-fold lower than those in vector transfectants. The increased apoptosis in HYAL1-v1 transfectants was due to the extrinsic pathway involving Fas and Fas-associated death domain up-regulation, caspase-8 activation, and BID cleavage, leading to caspase-9 and caspase-3 activation and poly(ADP-ribose) polymerase cleavage. When implanted in athymic mice, HYAL1-v1-expressing tumors grew 3- to 4-fold slower and tumor weights at day 35 were 3- to 6-fold less than the vector tumors (P < 0.001). Whereas vector tumors were infiltrating and had high mitoses and microvessel density, HYAL1-v1 tumors were necrotic, infiltrated with neutrophils, and showed low mitoses and microvessel density. Therefore, HYAL-v1 expression may negatively regulate bladder tumor growth, infiltration, and angiogenesis.

AB - Tumor cells express HYAL1 hyaluronidase, which degrades hyaluronic acid. HYAL1 expression in bladder cancer cells promotes tumor growth, invasion, and angiogenesis. We previously described five alternatively spliced variants of HYAL1 that encode enzymatically inactive proteins. The HYAL1-v1 variant lacks a 30-amino acid sequence that is present in HYAL1. In this study, we examined whether HYAL1-v1 expression affects bladder cancer growth and invasion by stably transfecting HT1376 bladder cancer cells with a HYAL1-v1 cDNA construct. Although HYAL1-v1 transfectants expressed equivalent levels of enzymatically active HYAL1 protein when compared with vector transfectants, their conditioned medium had 4-fold less hyaluronidase activity due to a noncovalent complex formed between HYAL1 and HYAL1-v1 proteins. HYAL1-v1 transfectants grew 3- to 4-fold slower due to cell cycle arrest in the G2-M phase and increased apoptosis. In HYAL1-v1 transfectants, cyclin B1, cdc2/p34, and cdc25c levels were ≥2-fold lower than those in vector transfectants. The increased apoptosis in HYAL1-v1 transfectants was due to the extrinsic pathway involving Fas and Fas-associated death domain up-regulation, caspase-8 activation, and BID cleavage, leading to caspase-9 and caspase-3 activation and poly(ADP-ribose) polymerase cleavage. When implanted in athymic mice, HYAL1-v1-expressing tumors grew 3- to 4-fold slower and tumor weights at day 35 were 3- to 6-fold less than the vector tumors (P < 0.001). Whereas vector tumors were infiltrating and had high mitoses and microvessel density, HYAL1-v1 tumors were necrotic, infiltrated with neutrophils, and showed low mitoses and microvessel density. Therefore, HYAL-v1 expression may negatively regulate bladder tumor growth, infiltration, and angiogenesis.

UR - http://www.scopus.com/inward/record.url?scp=33845759339&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33845759339&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-06-1121

DO - 10.1158/0008-5472.CAN-06-1121

M3 - Article

VL - 66

SP - 11219

EP - 11227

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 23

ER -