Adhesin Component Member STAG2 Enhances Cisplatin Tolerance in
Colorectal Cancer Cells through the Epithelial-Mesenchymal Transition
Pathway
Authors: Zhou Pengjun , Ye Meiyi , Chen Chunlan , Zhang Rong 
Published: July 2024

Background::

Platinum-based compounds are commonly used as an initial treatment for
colorectal cancer (CRC). However, the development of drug resistance in patients with CRC necessitates
the administration of high drug concentrations during clinical treatment, thereby augmenting
the toxicity of platinum-based compounds and increasing the mortality rate. STAG2 is a
significantly associated drug-resistance gene in many cancers, but it has not been studied in colorectal
cancer. Therefore, the present study aimed to investigate the role and drug sensitivity of
the cisplatin-resistant gene STAG2.

Methods::

The effects of STAG2 on drug resistance and survival rates of patients with CRC were
examined using the Genomics of Drug Sensitivity in Cancer (GDSC) and Kaplan-Meier (KM)
plotter databases. Subsequently, a sh-STAG2-HT-29 cell line was generated using a knockdown
test of STAG2, and the half-maximal inhibitory concentration (IC50) of the two cell lines was determined
using a cell viability test. We then used various techniques, including the Cell Counting
Kit-8 (CCK-8), plate cloning, 5-ethynyl-2’-deoxyuridine (EdU) fluorescence staining, flow cytometry
for cell cycle detection, the scar assay, the Transwell invasion assay, and Annexin V-fluorescein
isothiocyanate (FITC)/propidium iodide (PI) fluorescence staining for apoptosis detection,
to investigate the functionality of the four subgroups of cancer cell lines. Additionally, Western
blotting (WB) was used to identify the potential pathways associated with the observed functional
alterations. Finally, the phenotype, tumor weight, mouse weight, tumor volume, and tumor tissue
structure of the developed tumors were assessed using the subcutaneous tumor formation method.

Results::

Database analysis indicated that STAG2 plays a role in facilitating drug resistance among
individuals with CRC. Furthermore, mutations in this gene lead to increased sensitivity to cisplatin,
and its overexpression was associated with an unfavorable prognosis. Following the successful
development of STAG2 knockdown cells, differences in IC50 concentrations were observed
between HT-29 and sh-STAG2-HT-29 cells. A treatment concentration of 10 μM cisplatin
was selected, and the proliferation, migration, and invasion capabilities of cancer cells decreased
after STAG2 knockdown. Additionally, the sensitivity of the cells to cisplatin therapy was increased,
which was potentially mediated by the epithelial-mesenchymal transition (EMT) pathway.
In mice, the tumorigenic potential of HT-29 cells was reduced by STAG2 knockdown, accompanied
by a decrease in resistance to cisplatin therapy.

Conclusion::

STAG2 acts as a proto-oncogene in CRC, and its resistance to cisplatin therapy is
more prominent. This study confirmed the role of STAG2 in CRC and provided a theoretical basis
for the further development of STAG2 as an auxiliary criterion for determining dosage when patients
are treated with platinum drugs.