Therapeutic relevance of SOX9 stem cell factor in gastric cancer

ABSTRACT

Introduction: Recent comprehensive genetic and molecular profiling has identified molecular subtypes of gastric cancer (GC) and has linked them to clinical information. Moreover, SOX9 has been recently described as a relevant regulator of the population of GC stem cells (gCSCs), which are responsible for GC initiation and progression.

Areas covered: Through public data from The Cancer Genome Atlas (TCGA) project, the Asian Cancer Research Group (ACRG) and published studies, we link SOX9 expression to GC clinical information and molecular subtypes. We also discuss the role of deregulated SOX9 activity in critical aspects of GC progression, as well as therapy resistance. Finally, we provide information of the molecular mechanisms associated with its oncogenic activity.

Expert opinion: This review presents the clinical impact of SOX9 in GC and underscores the molecular mechanisms associated with its oncogenic activity. Current evidence highlights the key function of SOX9 in GC and postulates it as a prognostic factor, novel biomarker for patient stratification and a promising target. gCSCs are critical targets for GC eradication and SOX9 is a regulator of gCSCs; hence, the inhibition of SOX9 is a potential therapeutic strategy for GC, particularly for the MSS/TP53+ subgroup of patients in whom SOX9 expression correlates with poor outcome.

KEYWORDS:

• SOX9
• gastric cancer
• clinical stratification
• therapeutic target
• prognostic biomarker

Article Highlights

• Extensive molecular profiling has revealed the existence of several molecular GC subtypes exhibiting different outcomes.

• High levels of SOX9 drive GC progression and chemoresistance.

• High levels of SOX9 are associated with poor overall and disease-free survival in the MSS/TP53+ subgroup.

• SOX9 constitutes a novel biomarker for GC patient stratification.

• SOX9 or the molecular network responsible for its upregulation and pro-tumoral action is a potential therapeutic target for GC.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by grants from the Instituto Salud Carlos III and FEDER (CP10/00539, PI13/02277, CP16/00039, PI16/01580, DTS16/0184), the Brazilian National Council for Scientific and Technological Development (CNPq) (300975/2014-7), Diputacion Guipuzcoa, Industry Department of the Basque Government and postdoctoral and predoctoral (15/245) fellowships awarded by Stop Fuga de Cerebros (Roche) and University of the Basque Country to E Carrasco-Garcia and M García-Puga, respectively.