Life science
Medical & healthcare, Drug development

The meiosis-specific cohesion component stromal antigen 3 promoted
cell migration and chemoresistance in colorectal cancer
Department of Gastroenterological Surgery, Graduate School of Medicine
Assistant Professor Norikatsu Miyoshi

https://researchmap.jp/norProfessor Hidetoshi Eguchi

https://researchmap.jp/abcdabcdabcd

Life science

Abstract
We evaluated the prognostic impact and role of Stromal antigen(STAG) 3 in colorectal cancer (CRC). Analysis of 172 CRC surgical
specimens revealed that high STAG3 expression was associatedwith poor prognosis. STAG3 knockdown inhibited cell migrationand increased drug sensitivity to oxaliplatin, 5-fluorouracil, irinotecan hydrochloride hydrate, and BRAF inhibitor in CRC cell lines.
Moreover, suppression of STAG3 increased γH2AX foci, Our findings suggest that STAG3 is related to poor clinical outcomes andpromotes metastasis and chemotherapeutic resistance in CRC.
STAG3 may be a novel prognostic marker and potential therapeutictarget for CRC.

▍ Background & Results
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. A variety of treatment options
exist for patients with advanced CRC, depending on the identified
oncogenic mutations. BRAF mutations have been detected in approximately 10% of CRC and are related to poor prognosis andchemotherapy resistance. As BRAF inhibitors have been shown toimprove the survival in melanoma, their efficacy was recently also
demonstrated in BRAF-mutant CRC. Thus, we hypothesized thatSTAG components of the cohesin complex may be associated with
CRC. The cohesin subunit STAG has three paralogs in mammals:
mitosis-specific STAG1 and STAG2 and meiosis-specific STAG3.
While STAG1 expression correlates with carcinogenesis in CRC,
the association between STAG2 or STAG3 and CRC remains unknown. Therefore, we aimed to elucidate the relationships of STAG2and STAG3 to CRC, with a focus on changes in their expression.
Analysis of 172 CRC surgical specimens revealed that high
STAG3 expression was associated with poor prognosis. STAG3knockdown inhibited cell migration and increased drug sensitivity
to oxaliplatin, 5-fluorouracil, irinotecan hydrochloride hydrate, andBRAF inhibitor in CRC cell lines. The enhanced drug sensitivity
was also confirmed in a human organoid established from a CRC
specimen. Moreover, suppression of STAG3 increased γH2AXfoci. Particularly, in BRAF-mutant CRC cells, STAG3 silencing suppressed the expression of snail family transcriptional repressor 1and phosphorylation of extracellular signal-regulated kinase via
upregulation of dual-specificity phosphatase 6.

▍ Significance of the research and Future perspective
Our findings suggest that STAG3 is related to poor clinical outcomes and promotes metastasis and chemotherapeutic resistancein CRC. STAG3 may be a novel prognostic marker and potential
therapeutic target for CRC.

P a t e n t
Tr e a t i s e

Sasaki, Masaru; Miyoshi, Norikatsu; Fujino, Shiki et al. The meiosis-specific component stromal antigen 3 promotes cell migration and chemotherapeutic
resistance in colorectal cancer. Cancer Letters. 2021, 28; 497: 112-122. doi: 10.1016/j.canlet.2020.10.006

URL
K e y w o r d colorectal cancer, STAG3, chemotherapy, recurrence, prognossi