Spinster Homologue 2 Expression Correlates With Improved Patient Survival in Hepatocellular Carcinoma Despite Association With Lymph-Angiogenesis

Joy Sarkar; Masanori Oshi; Vikas Satyananda; Kohei Chida; Li Yan; Aparna Maiti; Nitai Hait; Itaru Endo; Kazuaki Takabe

doi:10.14740/wjon1732

Spinster Homologue 2 Expression Correlates With Improved Patient Survival in Hepatocellular Carcinoma Despite Association With Lymph-Angiogenesis

World J Oncol. 2024 Apr;15(2):181-191. doi: 10.14740/wjon1732. Epub 2024 Mar 21.

Authors

Joy Sarkar^{1

2}, Masanori Oshi^{1

3

2}, Vikas Satyananda¹, Kohei Chida¹, Li Yan⁴, Aparna Maiti¹, Nitai Hait¹, Itaru Endo³, Kazuaki Takabe^{1

3

5

6

7

8}

Affiliations

¹ Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
² These authors contributed equally to this work.
³ Department of Gastroenterological Surgery, Yokohama, Kanagawa 236-004, Japan.
⁴ Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
⁵ Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, the State University of New York, Buffalo, NY, USA.
⁶ Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan.
⁷ Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
⁸ Department of Breast Surgery, Fukushima Medical University, Fukushima, Japan.

Abstract

Background: Spinster homologue 2 (SPNS2) is a transporter of sphingosine-1-phosphate (S1P), a bioactive lipid linked to cancer progression. We studied the link between SPNS2 gene expression, tumor aggressiveness, and outcomes in patients with hepatocellular carcinoma (HCC).

Methods: Gene expression in patients with HCC was analyzed from the Cancer Genome Atlas (TCGA) (n = 350) and GSE76427 (n = 115) as a validation cohort, as well as liver tissue cohort GSE6764 (n = 75).

Results: High-SPNS2 HCC was significantly associated with high level of lymph-angiogenesis-related factors. SPNS2 expression was significantly higher in normal liver and early HCC versus advanced HCC (P < 0.02). High SPNS2 levels enriched immune response-related gene sets; inflammatory, interferon (IFN)-α, IFN-γ responses, and tumor necrosis factor (TNF)-α, interleukin (IL)-6/Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling, complement and allograft rejection, but did not significantly infiltrate specific immune cells nor cytolytic activity score. High-SPNS2 HCC enriched tumor aggravating pathway gene sets such as KRAS (Kirsten rat sarcoma virus) signaling, but inversely correlated with Nottingham histological grade, MKI67 (marker of proliferation Ki-67) expression, and cell proliferation-related gene sets. Further, high-SPNS2 HCC had significantly high infiltration of stromal cells, showing that low-SPNS2 HCC is highly proliferative. Finally, high-SPNS2 HCC was associated with better disease-free, disease-specific, and overall survival (P = 0.031, 0.046, and 0.040, respectively).

Conclusions: Although SPNS2 expression correlated with lymph-angiogenesis and other cancer-promoting pathways, it also enriched immune response. SPNS2 levels were higher in normal liver compared to HCC, and inversely correlated with cancer cell proliferation and better survival. SPNS2 expression may be beneficial in HCC patients despite detrimental in-vitro effects.

Keywords: Gene set enrichment analysis; Hepatocellular carcinoma; Immune response; Lymph-angiogenesis; Proliferation; SPNS2; Sphingosine-1-phosphate.

Grants and funding

KT was supported by the US NIH grant R01CA160688. Roswell Park Comprehensive Cancer Center is supported by NCI/NIH grant P30-CA016056.