SPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma

Ki-Fong Man, Lei Zhou, Huajian Yu, Ka-Hei Lam, Wei Cheng, Jun Yu, Terence K. Lee, Jing-Ping Yun, Xin-Yuan Guan, Ming Liu and Stephanie Ma ()
Additional contact information
Ki-Fong Man: The University of Hong Kong
Lei Zhou: The University of Hong Kong – Shenzhen Hospital
Huajian Yu: The University of Hong Kong
Ka-Hei Lam: The University of Hong Kong
Wei Cheng: Guangzhou Medical University
Jun Yu: The Chinese University of Hong Kong
Terence K. Lee: The Hong Kong Polytechnic University
Jing-Ping Yun: Sun Yat-Sen University Cancer Centre
Xin-Yuan Guan: The University of Hong Kong – Shenzhen Hospital
Ming Liu: Guangzhou Medical University
Stephanie Ma: The University of Hong Kong

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Tumor lineage plasticity, considered a hallmark of cancer, denotes the phenomenon in which tumor cells co-opt developmental pathways to attain cellular plasticity, enabling them to evade targeted therapeutic interventions. However, the underlying molecular events remain largely elusive. Our recent study identified CD133/Prom1 in hepatocellular carcinoma (HCC) tumors to mark proliferative tumor-propagating cells with cancer stem cell-like properties, that follow a dedifferentiation trajectory towards a more embryonic state. Here we show SPINK1 to strongly associate with CD133 + HCC, and tumor dedifferentiation. Enhanced transcriptional activity of SPINK1 is mediated by promoter binding of ELF3, which like CD133, is found to increase following 5-FU and cisplatin treatment; while targeted depletion of CD133 will reduce both ELF3 and SPINK1. Functionally, SPINK1 overexpression promotes tumor initiation, self-renewal, and chemoresistance by driving a deregulated EGFR-ERK-CDK4/6-E2F2 signaling axis to induce dedifferentiation of HCC cells into their ancestral lineages. Depleting SPINK1 function by neutralizing antibody treatment or in vivo lentivirus-mediated Spink1 knockdown dampens HCC cancer growth and their ability to resist chemotherapy. Targeting oncofetal SPINK1 may represent a promising therapeutic option for HCC treatment.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-43670-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43670-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-43670-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().