Article Data

  • Views 995
  • Dowloads 132

Original Research

Open Access

High expression of SPINT2 promotes immune infiltration and tumor progression in ovarian cancer

  • Lin Luo1
  • Wei He1
  • Chunyan Wang1,*,

1Gynaecology, Sichuan Provincial Center for Gynaecology & Breast Disease, Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China

DOI: 10.22514/ejgo.2023.086 Vol.44,Issue 5,October 2023 pp.116-124

Submitted: 14 June 2023 Accepted: 14 July 2023

Published: 15 October 2023

*Corresponding Author(s): Chunyan Wang E-mail: cywang7719@163.com

Abstract

This study aimed to identify the function and mechanism of Serine Peptidase Inhibitor, Kunitz Type 2 (SPINT2) in ovarian cancer (OC). The expression of SPINT2 was analyzed using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify enriched functional categories of SPINT2 and its correlated genes. Correlation of SPINT2 with OC immune infiltration level was analyzed using the Tumor IMmune Estimation Resource (TIMER) web server. The effect of SPINT2 on cell proliferation was detected using cell counting kit-8 (CCK-8) and colony formation assay. Its effects on cell migration and invasion were examined using the transwell assay. Function of SPINT2 in M2 macrophage recruitment was detected using the migration assay. The role of SPINT2 on M2 macrophage differentiation was evaluated using M2 macrophage markers and by detection of interleukin 10 (IL-10) release. An OC cohort study (GSE12470) showed that SPINT2 was highly expressed in OC. The high SPINT2 expression was related to shorter overall survival (OS) and poor recurrence-free survival (RFS). GO and KEGG analysis indicated that SPINT2 associated genes played roles in glycoprotein catabolism, cell adhesion and T cell differentiation. SPINT2 also played a key role in infiltration of macrophages in OC. shSPINT2 reduced viability and colony formation ability of ovarian cancer cell line SK-OV-3 cells. Moreover, shSPINT2 also inhibited the cell migration and invasion. Co-culture of shSPINT2 transfected SK-OV-3 cells with macrophages inhibited the migration of M2 macrophages, and inhibited macrophages polarization from M0 to M2. These results suggested that SPINT2 is involved in infiltration of tumor-associated macrophages (TAMs). SPINT2 also plays an important role in the polarization and migration of macrophages. These findings suggested that SPINT2 has the potential to be explored as a biomarker for OC and a potential target.


Keywords

SPINT2; TAMs; Ovarian cancer


Cite and Share

Lin Luo,Wei He,Chunyan Wang. High expression of SPINT2 promotes immune infiltration and tumor progression in ovarian cancer. European Journal of Gynaecological Oncology. 2023. 44(5);116-124.

References

[1] Reid BM, Permuth JB, Sellers TA. Epidemiology of ovarian cancer: a review. Cancer Biology & Medicine. 2017; 14: 9–32.

[2] Chen S, Wang L, Sun K, Liu Y, Guan X, Zong Z, et al. LncRNA PCGEM1 induces ovarian carcinoma tumorigenesis and progression through RhoA pathway. Cellular Physiology and Biochemistry. 2018; 47: 1578–1588.

[3] Meys EMJ, Jeelof LS, Ramaekers BLT, Dirksen CD, Kooreman LFS, Slangen BFM, et al. Economic evaluation of an expert examiner and different ultrasound models in the diagnosis of ovarian cancer. European Journal of Cancer. 2018; 100: 55–64.

[4] Partridge EE, Phillips JL, Menck HR. The national cancer data base report on ovarian cancer treatment in United States hospitals. Cancer. 1996; 78: 2236–2246.

[5] Kurnit KC, Fleming GF, Lengyel E. Updates and new options in advanced epithelial ovarian cancer treatment. Obstetrics & Gynecology. 2021; 137: 108–121.

[6] Kuroki L, Guntupalli SR. Treatment of epithelial ovarian cancer. BMJ. 2020; 371: m3773.

[7] Nikolaidi A, Fountzilas E, Fostira F, Psyrri A, Gogas H, Papadimitriou C. Neoadjuvant treatment in ovarian cancer: new perspectives, new challenges. Frontiers in Oncology. 2022; 12: 820128.

[8] Bronger H. Immunology and immune checkpoint inhibition in ovarian cancer—current aspects. Geburtshilfe Frauenheilkd. 2021; 81: 1128–1144. (In German)

[9] Yang Y, Zhao T, Chen Q, Li Y, Xiao Z, Xiang Y, et al. Nanomedicine strategies for heating “cold” ovarian cancer (OC): next evolution in immunotherapy of OC. Advanced Science. 2022; 9: e2202797.

[10] Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. Journal of Hematology & Oncology. 2019; 12: 76.

[11] He Z, Zhang S. Tumor-associated macrophages and their functional transformation in the hypoxic tumor microenvironment. Frontiers in Immunology. 2021; 12: 741305.

[12] Anfray C, Ummarino A, Andón FT, Allavena P. Current strategies to target tumor-associated-macrophages to improve anti-tumor immune responses. Cells. 2019; 9: 46.

[13] Tong N, He Z, Ma Y, Wang Z, Huang Z, Cao H, et al. Tumor associated macrophages, as the dominant immune cells, are an indispensable target for immunologically cold tumor—glioma therapy? Frontiers in Cell and Developmental Biology. 2021; 9: 706286.

[14] KHABIPOV A, KÄDING A, LIEDTKE KR, FREUND E, PARTECKE L, BEKESCHUS S. RAW 264.7 macrophage polarization by pancreatic cancer cells—a model for studying tumour-promoting macrophages. Anticancer Research. 2019; 39: 2871–2882.

[15] Hatzold J, Wessendorf H, Pogoda H, Bloch W, Hammerschmidt M. The Kunitz-type serine protease inhibitor SPINT2 is required for cellular cohesion, coordinated cell migration and cell survival during zebrafish hatching gland development. Developmental Biology. 2021; 476: 148–170.

[16] Roversi FM, Olalla Saad ST, Machado-Neto JA. Serine peptidase inhibitor Kunitz type 2 (SPINT2) in cancer development and progression. Biomedicine & Pharmacotherapy. 2018; 101: 278–286.

[17] Ramirez Alvarez C, Kee C, Sharma AK, Thomas L, Schmidt FI, Stanifer ML, et al. The endogenous cellular protease inhibitor SPINT2 controls SARS-CoV-2 viral infection and is associated to disease severity. PLOS Pathogens. 2021; 17: e1009687.

[18] Parr C, Watkins G, Mansel RE, Jiang WG. The hepatocyte growth factor regulatory factors in human breast cancer. Clinical Cancer Research. 2004; 10: 202–211.

[19] Wu Q, Yin G, Luo J, Zhang Y, Ai T, Tian J, et al. Comprehensive analysis of the expression and prognostic value of SPINT1/2 in breast carcinoma. Frontiers in Endocrinology. 2021; 12: 665666.

[20] Graumann J, Finkernagel F, Reinartz S, Stief T, Brödje D, Renz H, et al. Multi-platform affinity proteomics identify proteins linked to metastasis and immune suppression in ovarian cancer plasma. Frontiers in Oncology. 2019; 9: 1150.

[21] Chandrashekar DS, Karthikeyan SK, Korla PK, Patel H, Shovon AR, Athar M, et al. UALCAN: an update to the integrated cancer data analysis platform. Neoplasia. 2022; 25: 18–27.

[22] Lánczky A, Győrffy B. Web-based survival analysis tool tailored for medical research (KMplot): development and implementation. Journal of Medical Internet Research. 2021; 23: e27633.

[23] Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Research. 2017; 77: e108–e110.

[24] Uhlén M, Björling E, Agaton C, Szigyarto CA, Amini B, Andersen E, et al. A human protein atlas for normal and cancer tissues based on antibody proteomics. Molecular & Cellular Proteomics. 2005; 4: 1920–1932.


Abstracted / indexed in

Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,500 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.

Biological Abstracts Easily discover critical journal coverage of the life sciences with Biological Abstracts, produced by the Web of Science Group, with topics ranging from botany to microbiology to pharmacology. Including BIOSIS indexing and MeSH terms, specialized indexing in Biological Abstracts helps you to discover more accurate, context-sensitive results.

Google Scholar Google Scholar is a freely accessible web search engine that indexes the full text or metadata of scholarly literature across an array of publishing formats and disciplines.

JournalSeek Genamics JournalSeek is the largest completely categorized database of freely available journal information available on the internet. The database presently contains 39226 titles. Journal information includes the description (aims and scope), journal abbreviation, journal homepage link, subject category and ISSN.

Current Contents - Clinical Medicine Current Contents - Clinical Medicine provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in clinical medicine.

BIOSIS Previews BIOSIS Previews is an English-language, bibliographic database service, with abstracts and citation indexing. It is part of Clarivate Analytics Web of Science suite. BIOSIS Previews indexes data from 1926 to the present.

Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.

Submission Turnaround Time

Conferences

Top