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Research article
Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma
Qingan Jia
Xi'an Jiaotong University Medical College First Affiliated Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3256-7197
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Cancer.
Background: Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. Methods: The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ABCG1 and Wnt signaling in oxaliplatin resistance were confirmed. Results: Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding the ATP-binding cassette transporter G1 ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. Conclusions: These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.
Keywords
Hepatocellular carcinoma，Oxaliplatin resistance，Saracatinib，Wnt signaling，ABCG1
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CURRENT STATUS: Published
Version 5
Posted 03 Jan, 2020
Published
On 13 Jan, 2020
No community comments so far
Submission checks complete
On 18 Dec, 2019
Editorial decision: Accept
On 18 Dec, 2019
No comments provided
Editorial decision: Minor revision
On 16 Dec, 2019
Editor assigned
On 13 Dec, 2019
Submission checks complete
On 12 Dec, 2019
Editor invited
On 12 Dec, 2019
No comments provided
Editorial decision: Minor revision
On 09 Dec, 2019
Editor assigned
On 08 Dec, 2019
Submission checks complete
On 07 Dec, 2019
Editor invited
On 07 Dec, 2019
No comments provided
Editorial decision: Minor revision
On 26 Nov, 2019
Review #2 received
Received 23 Nov, 2019
Review #1 received
Received 19 Nov, 2019
Reviewer #2 agreed
On 10 Nov, 2019
Reviewers invited
Invitations sent on 05 Nov, 2019
Reviewer #1 agreed
On 05 Nov, 2019
Editor assigned
On 30 Oct, 2019
Submission checks complete
On 29 Oct, 2019
Editor invited
On 29 Oct, 2019
No comments provided
Editorial decision: Major revision
On 21 Oct, 2019
Review #3 received
Received 13 Oct, 2019
Review #1 received
Received 30 Aug, 2019
Review #2 received
Received 21 Aug, 2019
Reviewer #3 agreed
On 17 Aug, 2019
Reviewer #2 agreed
On 16 Aug, 2019
Reviewer #1 agreed
On 22 Jul, 2019
Reviewers invited
Invitations sent on 22 Jul, 2019
Editor assigned
On 27 Jun, 2019
Submission checks complete
On 12 Jun, 2019
Editor invited
On 12 Jun, 2019
First submitted
On 30 May, 2019
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
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This preprint is under consideration at BMC Cancer. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma
Qingan Jia
Xi'an Jiaotong University Medical College First Affiliated Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3256-7197
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 5
Posted 03 Jan, 2020
Published
On 13 Jan, 2020
No community comments so far
Submission checks complete
On 18 Dec, 2019
Editorial decision: Accept
On 18 Dec, 2019
No comments provided
Editorial decision: Minor revision
On 16 Dec, 2019
Editor assigned
On 13 Dec, 2019
Submission checks complete
On 12 Dec, 2019
Editor invited
On 12 Dec, 2019
No comments provided
Editorial decision: Minor revision
On 09 Dec, 2019
Editor assigned
On 08 Dec, 2019
Submission checks complete
On 07 Dec, 2019
Editor invited
On 07 Dec, 2019
No comments provided
Editorial decision: Minor revision
On 26 Nov, 2019
Review #2 received
Received 23 Nov, 2019
Review #1 received
Received 19 Nov, 2019
Reviewer #2 agreed
On 10 Nov, 2019
Reviewers invited
Invitations sent on 05 Nov, 2019
Reviewer #1 agreed
On 05 Nov, 2019
Editor assigned
On 30 Oct, 2019
Submission checks complete
On 29 Oct, 2019
Editor invited
On 29 Oct, 2019
No comments provided
Editorial decision: Major revision
On 21 Oct, 2019
Review #3 received
Received 13 Oct, 2019
Review #1 received
Received 30 Aug, 2019
Review #2 received
Received 21 Aug, 2019
Reviewer #3 agreed
On 17 Aug, 2019
Reviewer #2 agreed
On 16 Aug, 2019
Reviewer #1 agreed
On 22 Jul, 2019
Reviewers invited
Invitations sent on 22 Jul, 2019
Editor assigned
On 27 Jun, 2019
Submission checks complete
On 12 Jun, 2019
Editor invited
On 12 Jun, 2019
First submitted
On 30 May, 2019
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Cancer.
Background: Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. Methods: The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ABCG1 and Wnt signaling in oxaliplatin resistance were confirmed. Results: Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding the ATP-binding cassette transporter G1 ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. Conclusions: These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.
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Figure 5