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Int J Biol Sci 2023; 19(9):2772-2786. doi:10.7150/ijbs.79126 This issue Cite

Research Paper

Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation

Yi-Ru Pan1,*, Chiao-En Wu2,7,*, Shih-Ming Jung3, Shih-Chiang Huang3, Sheng-Hsuan Lin1, Wen-Chi Chou2, Yu-Chan Chang4, Ming-Huang Chen5,6, Tsai-Hsien Hung7, Alice L. Yu7,8, Wen-Kuan Huang2,✉, Chun-Nan Yeh1,7,9,✉

1. Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan 333, Taiwan.
2. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
3. Department of Pathology, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
4. Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
5. Center for Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
6. School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
7. Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taiwan.
8. Department of Pediatrics, University of California in San Diego, San Diego, CA 92103, USA.
9. School of Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan.
* These authors contributed equally to this work.

✉ Corresponding authors: Wen-Kuan Huang (medfoxtaiwancom); Chun-Nan Yeh (yehchunnancom).

Citation:
Pan YR, Wu CE, Jung SM, Huang SC, Lin SH, Chou WC, Chang YC, Chen MH, Hung TH, Yu AL, Huang WK, Yeh CN. Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation. Int J Biol Sci 2023; 19(9):2772-2786. doi:10.7150/ijbs.79126. https://www.ijbs.com/v19p2772.htm
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Abstract

Graphic abstract

Cholangiocarcinoma (CCA) exhibits aggressive biological behavior and a poor prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line chemotherapy for advanced CCA but has a response rate of only 20-30%. Therefore, investigating treatments to overcome GEM resistance in advanced CCA is crucial. Among mucin (MUC) family members, MUC4 showed the greatest increase in the resistant versus parental sublines. MUC4 was upregulated in whole-cell lysates and conditioned media from gemcitabine-resistant (GR) CCA sublines. MUC4 mediated GEM resistance by activating AKT signaling in GR CCA cells. The MUC4-AKT axis induced BAX S184 phosphorylation to inhibit apoptosis and downregulated GEM transporter human equilibrative nucleoside transporter 1 (hENT1) expression. The combination of AKT inhibitors and GEM or afatinib overcame GEM resistance in CCA. In vivo, capivasertib (an AKT inhibitor) increased GEM sensitivity in GR cells. MUC4 promoted EGFR and HER2 activation to mediate GEM resistance. Finally, MUC4 expression in patient plasma correlated with MUC4 expression. Paraffin-embedded specimens from non-responders expressed significantly more MUC4 than did those from responders, and this upregulation was associated with poor progression-free survival and overall survival. In GR CCA, high MUC4 expression promotes sustained EGFR/HER2 signaling and AKT activation. The combination of AKT inhibitors with GEM or afatinib might overcome GEM resistance.

Keywords: Mucin 4, plasma, cholangiocarcinoma, GEM resistance, AKT inhibitor

Citation styles

APA
Pan, Y.R., Wu, C.E., Jung, S.M., Huang, S.C., Lin, S.H., Chou, W.C., Chang, Y.C., Chen, M.H., Hung, T.H., Yu, A.L., Huang, W.K., Yeh, C.N. (2023). Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation. International Journal of Biological Sciences, 19(9), 2772-2786. https://doi.org/10.7150/ijbs.79126.

ACS
Pan, Y.R.; Wu, C.E.; Jung, S.M.; Huang, S.C.; Lin, S.H.; Chou, W.C.; Chang, Y.C.; Chen, M.H.; Hung, T.H.; Yu, A.L.; Huang, W.K.; Yeh, C.N. Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation. Int. J. Biol. Sci. 2023, 19 (9), 2772-2786. DOI: 10.7150/ijbs.79126.

NLM
Pan YR, Wu CE, Jung SM, Huang SC, Lin SH, Chou WC, Chang YC, Chen MH, Hung TH, Yu AL, Huang WK, Yeh CN. Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation. Int J Biol Sci 2023; 19(9):2772-2786. doi:10.7150/ijbs.79126. https://www.ijbs.com/v19p2772.htm

CSE
Pan YR, Wu CE, Jung SM, Huang SC, Lin SH, Chou WC, Chang YC, Chen MH, Hung TH, Yu AL, Huang WK, Yeh CN. 2023. Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation. Int J Biol Sci. 19(9):2772-2786.

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