Intrinsic and Acquired Paclitaxel Resistance in Esophageal Squamous Cancer Cells
Hongjin Wu1,2, Mingfeng Jiang2, Ying
Li1,2, Robbi Sanchez3, Ziwei
Li1, Juehua Yu2,3*, F. Charles Brunicardi3*
1International Research Center for Regenerative
Medicine, BOAO International Hospital, Hainan, P.R. China
2Cancer Research Institute, Hangzhou Cancer
Hospital, Hangzhou, Zhejiang, P.R. China
3Department of Surgery, College of Medicine and
Life Sciences, University of Toledo, Toledo, Ohio, USA
*Corresponding author(s): Juehua Yu, Cancer Research Institute, Hangzhou Cancer
Hospital, Hangzhou, 320000, Zhejiang, P.R. China. Tel: +8613757186599; Email: juehuayu@gmail.com;
F. Charles Brunicardi, Department of
Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo,
43614, Ohio, USA. Tel: +1 4193439398; Email: Francis.Brunicardi@utoledo.edu
Editorial
Single-cell transcriptomes analyses lead to a more accurate representation of
cell-to-cell variations instead of the stochastic average reflected by bulk
measurements [1]. It has been a promising technique to identify subpopulations in
a multicellular system. In the paired paclitaxel sensitive and resistance
cancer cell lines, Esophageal Squamous Cancer (ESCC) cell line KYSE-30 and
Taxol-R-KYSE-30, single-cell and bulk transcriptome analysis were performed
respectively, indicating that the categorization of cancer subpopulations with
intrinsic and acquired paclitaxel resistance could be marked with the
expression level of KRT19 and proteasome genes, respectively. This study
provides a novel finding for the heterogeneity of esophageal cancer cells in
response to paclitaxel treatment at single-cell transcriptome level, which
could improve the understanding of molecular mechanisms involved in
paclitaxel-resistance.
In primary KYSE-30
cancer cells, we identified and validated that KRT19 was a cell surface marker
for the intrinsic paclitaxel resistance, which is consistent with the study
from Qiao. YF et al. reporting that KRT19 mRNA level negatively correlated with
prognosis of ESCC patients [2]. In addition, De Angelis PM. et al. reported that KRT19 was involved in
response to 5-FU therapies [3].
We also found that KRT19 was related to worse prognosis in KIRC, LUAD and PAAD
in database of OncoLnc (www.oncolnc.org), and the expression level of KRT19 was
correlated with the survival of lung squamous carcinoma and gastric carcinoma
which were treated with chemotherapy in the Kaplan Meier plotter (http://kmplot.com/). Another cell surface
marker in the intrinsic paclitaxel resistant cancer cells was CD40, which can
inhibit paclitaxel-induced apoptosis in breast cancer [4-6]. Furthermore, we
analyzed all the highly expressed genes in intrinsic paclitaxel resistant
cancer cells. These genes were significantly enriched in the signaling of
pathway in cancer (p-value = 0.0075) and transcriptional dysregulation in
cancer (p-value = 0.035). However, the contributory roles and detailed
mechanisms to paclitaxel resistance of biomarkers (KRT19 and CD40) and affected
signaling pathways still need to be assessed in the future studies.
In the resistant
cancer cells (Taxol-R-KYSE-30), low level expression of HIF-1a signaling and
high expression of proteasome signaling were identified to be responsible for
their paclitaxel resistance. The expression level of proteasome genes was
significantly enriched in the Taxol-R-KYSE-30, and the correlation of high
proteasome activation and paclitaxel resistance was also reported in other
studies [7-9]. We also found that diverse expression of proteasome genes in the
TCGA database of ESCC patients (Figure A). Some ESCC patients have high expression level of proteasome
genes, and they correlate with poor prognosis (Figure B), which may be due to
the primary resistance to therapeutic treatments.
Taking together, although paclitaxel has been widely used as a first-line
therapeutic strategy in ESCC, even in combination with other chemical drugs,
the overall survival is still to be improved. In that case, more precise
treatment for ESCC patients need be considered to avoid the intrinsic and
acquired paclitaxel resistance (Figure C). The markers KRT19, CD40 and proteasome genes that we identified
for intrinsic and acquired paclitaxel resistance of ESCC, should be
investigated before the treatment of paclitaxel. Classification of ESCC
patients into paclitaxel sensitive or resistant groups will lead to improved
treatment. And for the intrinsic paclitaxel resistance, the combination of
target therapy and proteasome inhibitors could be a novel approach for the
clinical treatment of ESCC.
A. RNA expression of
proteasome signaling genes in TCGA database of ESCC (PMID: 28052061),
Expression ratio = Log2(FPKM). The ESCC patients were clustered into three
subgroups according to the expression level of proteasome genes (Low
Proteasome, High Proteasome, and Moderate Proteasome). The majority of ESCC
patients show moderate expression of proteasome genes.
B. Highly expressed proteasome genes correlate with poor prognosis and overall survival in TCGA. The overall survival of patients with moderate expression of proteasome genes were much longer than the patients with high expression of proteasome genes, but shorter than the patients with low expression of proteasome genes.
C. Suggested improved therapeutic strategies for ESCC treatment. Tumor tissues of ESCC patients were obtained with biopsy, and the expression of KRT19, CD40, and proteasome genes were investigated with qRT-PCR or RNA-seq or Immunohistochemistry. Patients with low expression of KRT19, CD40 and proteasome genes can be directly treated with paclitaxel; patients with high expression of KRT19 and CD40 need to be treated with paclitaxel in combination with other targeted therapies (Targeting KRT19 or CD40); patients with high expression of proteasome genes need to be treated with paclitaxel in combination with proteasome inhibitors. After several rounds of treatments, tumor tissues could be investigated again on the expression of proteasome genes.
Figure 1: Precision treatment for ESCC.