Stomatin-like Protein 2 Promotes Tumor Cell Survival by Activating the JAK2-STAT3-PIM1 Pathway, Suggesting a Novel Therapy in CRC

Qiang Liu; Anqi Li; Lisha Wang; Wei He; Ling Zhao; Chao Wu; Shasha Lu; Xuanguang Ye; Huiyong Zhao; Xiaohan Shen; Xiuying Xiao; Zebing Liu

doi:10.1016/j.omto.2020.03.010

Stomatin-like Protein 2 Promotes Tumor Cell Survival by Activating the JAK2-STAT3-PIM1 Pathway, Suggesting a Novel Therapy in CRC

Mol Ther Oncolytics. 2020 Mar 30:17:169-179. doi: 10.1016/j.omto.2020.03.010. eCollection 2020 Jun 26.

Authors

Qiang Liu¹, Anqi Li², Lisha Wang³, Wei He¹, Ling Zhao¹, Chao Wu⁴, Shasha Lu⁵, Xuanguang Ye⁶, Huiyong Zhao⁴, Xiaohan Shen⁷, Xiuying Xiao⁸, Zebing Liu¹

Affiliations

¹ Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
² Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
³ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁴ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁵ Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
⁶ Department of Pathology, Jinshan Hospital of Fudan University, Shanghai 201508, China.
⁷ Department of Diagnosis, Ningbo Diagnostic Pathology Center, Ningbo 315021, China.
⁸ Department of Oncology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.

Abstract

Despite intensive efforts, a considerable proportion of colorectal cancer (CRC) patients develop local recurrence and distant metastasis. Stomatin-like protein 2 (SLP-2), a member of the highly conserved stomatin superfamily, is upregulated across cancer types. However, the biological and functional roles of SLP-2 remain elusive in CRC. Here, we report that high SLP-2 expression was found in CRC tissues and was linked to tumor progression and tumor cell differentiation. Additionally, high SLP-2 expression correlated with poor overall survival (OS) in CRC patients (p < 0.001). SLP-2 knockout (SLP-2KO), generated by CRISPR/Cas9, reduced cell growth, migration, and invasion; induced apoptosis in CRC cells; and reduced tumor xenograft growth in vivo. A 181-compound library screening showed that SLP-2KO produced resistance to JAK2 inhibitors (NVP-BSK805 and TG-101348) and a PIM1 inhibitor (SGI-1776), revealing that the JAK2-STAT3-PIM1 oncogenic pathway was potentially controlled by SLP-2 in CRC. In vitro and in vivo, TG-101348 combined with SGI-1776 was synergistic in CRC (combination index [CI] < 1). Overall, our findings suggest that SLP-2 controls the JAK2-STAT3-PIM1 oncogenic pathway, offering a rationale for a novel therapeutic strategy with combined SGI-1776 and TG-101348 in CRC. Additionally, SLP-2 may be a prognostic marker and biomarker for sensitivity to JAK2 and PIM1 inhibitors.

Keywords: JAK2; PIM1; STAT3; colorectal cancer; stomatin-like protein 2.

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States