Evidence map›Paper›PMID 36581895›Full record

ArticleCancer cell international2022

Targeting hyaluronic acid synthase-3 (HAS3) for the treatment of advanced renal cell carcinoma.

Jiaojiao Wang, Andre R Jordan, Huabin Zhu, Sarrah L Hasanali, Eric Thomas, Soum D Lokeshwar, Daley S Morera, Sung Alexander, Joseph McDaniels, Anuj Sharma and 8 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer cell international, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
2.4field-weighted citation impact, top 9% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed, 25 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 5 institutions in 1 country.

Jiaojiao Wang *Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Andre R Jordan *Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Huabin ZhuDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Sarrah L HasanaliDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Eric ThomasDivision of Urology, Department of Surgery, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Augusta, GA, 30912, USA.
Soum D LokeshwarDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Daley S MoreraDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Sung AlexanderDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Joseph McDanielsDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Anuj SharmaDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Karina AguilarDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Semih SarcanDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Tianyi ZhuGreenbrier High School, Evans, GA, 30809, USA.
Mark S SolowayMemorial Healthcare System, Aventura, FL, 33180, USA.
Martha K TerrisDivision of Urology, Department of Surgery, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Augusta, GA, 30912, USA.
Muthusamy ThangarajuDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Luis E LopezDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA.
Vinata B LokeshwarDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN 1177A, Augusta, GA, 30912, USA. vlokeshwar@augusta.edu.
Augusta University · USMemorial Healthcare System · USMethodist Hospital · USTulane University · USYale University · US

Funding

Novel Biomarkers for the Clinical Management of Bladder CancerR01CA227277 · NCI · AUGUSTA UNIVERSITY · PI LOKESHWAR, VINATA B · 2018 to 2023
$2.2M
Dietary Combination For Prevention of Metastatic Renal Cell CarcinomaR01CA176691 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI LOKESHWAR, VINATA B · 2014 to 2019
$1.7M
NCI NIH HHS R01 CA227277NIH HHS 5R01CA176691-05
6 · The paper itself

Abstract

backgroundHyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment.

methodsWe analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts.

resultsRCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant.

conclusionHAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6-1.1-g/day), SF targets HAS3 and effectively abrogates mRCC.

Indexed as

4-methylumbelliferoneHAS3Hyaluronic acidMolecular targetingRenal cell carcinomaSorafenib

Identifiers

PMID36581895
PMCPMC9801563
OpenAlexW4313288612

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.