Downregulation of SPINK5 promotes laryngeal cancer cell malignancy through activation of KLK6-dependent glycolysis

Sep 22, 2026

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Laryngeal cancer remains difficult to treat, with constrained options and frequent recurrence, metastasis, and therapeutic resistance. This study investigates how serine protease inhibitor Kazal type 5 (SPINK5) influences laryngeal cancer progression and metabolic reprogramming. Analysis of TCGA data, immunohistochemistry, and multiple cellular assays evaluates SPINK5 expression, glycolytic mediators, and cell growth and migration, testing pathway dependence via KLK6 silencing.

LanguageEnglish

CategoryHealthcare

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Pages15

Reading Time38 min

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Abstract

Background

Methods

Results

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Introduction

Sun et al. BMC Cancer (2026) 26:764 BMC Cancer [https://doi.org/10.1186/s12885-026-15958-8](https://doi.org/10.1186/s12885-026-15958-8) RESEARCH Open Access Downregulation of SPINK5 promotes laryngeal cancer cell malignancy through activation of KLK6-dependent glycolysis Jianing Sun1, Wudan He1, Shanshan Sun1, Dijiang Ma1* and Lili Fang1* Abstract Background Laryngeal cancer remains a significant health challenge with limited therapeutic options. Serine protease inhibitor Kazal type 5 (SPINK5) is implicated as a tumor suppressor in head and neck cancers, yet its role in laryngeal cancer progression and metabolic reprogramming remains unclear. This study aimed to define SPINK5’s function and molecular mechanism in laryngeal cancer progression. Methods Analysis of The Cancer Genome Atlas (TCGA) data and immunohistochemistry was conducted to investigate the expression level of SPINK family members in laryngeal cancer tissues compared to adjacent nontumorous tissues. Besides, western blotting, CCK-8, colony formation, and migration assay were used to investigate the expression of SPINK5, Glucose Transporter 1 (GLUT1), and Hexokinase II (HK-II), and growth and migration capacities of laryngeal cancer cells. While glucose uptake and lactate secretion detection were conducted to measure the glycolysis level of laryngeal cancer cells. And differences among groups were analyzed using Student’s t-test or one-way analysis of variance. Results The downregulation of SPINK5 was observed in laryngeal cancer tissues compared to adjacent nontumorous tissues. SPINK5 acted as a tumor suppressor, inhibiting laryngeal cancer cell growth and migration. Mechanistically, SPINK5 knockdown promoted glycolysis through GLUT1 and HK-II upregulation. Notably, SPINK5 could interact with kallikrein-related peptidase 6 (KLK6) . SPINK5 knockdown enhanced the activity of KLK6 and the activation of the PI3K/AKT/mTOR signaling pathway in laryngeal cancer cells. Critically, silencing KLK6 reversed the oncogenic effects induced by SPINK5 knockdown, including PI3K/AKT/mTOR pathway activation, enhanced glycolysis, and accelerated cell growth and migration. Conclusions These findings identify a novel SPINK5-KLK6-glycolysis regulatory axis driving laryngeal cancer progression. Our results highlight SPINK5 as a tumor suppressor gene for laryngeal cancer progression, providing new insights into its molecular pathogenesis. Keywords Laryngeal cancer, SPINK5, Glycolysis, KLK6, Tumor progression *Correspondence: Dijiang Ma [adibaba@163.com](adibaba@163.com)[ ](adibaba@163.com)Lili Fang [fanglilixym@163.com](fanglilixym@163.com) 1Yangming Hospital Affiliated to Ningbo University (Yuyao People’s Hospital), Zhejiang 315400, China © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/.)[.](http://creativecommons.org/licenses/by/4.0/.) Sun et al. BMC Cancer (2026) 26:764 Introduction Laryngeal cancer is one of the most common malignancies within head and neck squamous cell carcinomasand represents the second most common respiratory tract cancer after lung cancer [1]. Despite advances in treatment modal

FAQs

What role does SPINK5 downregulation play in laryngeal cancer progression?

SPINK5 downregulation is observed in laryngeal cancer tissues, and SPINK5 acts as a tumor suppressor that inhibits cancer cell growth and migration.

How does SPINK5 affect glycolysis-related metabolism?

SPINK5 knockdown promotes glycolysis by upregulating GLUT1 and HK-II, increasing glycolytic activity measured through glucose uptake and lactate secretion.

Why is KLK6 important in the SPINK5 mechanism?

SPINK5 can interact with KLK6. Silencing KLK6 reverses the oncogenic effects caused by SPINK5 knockdown, including PI3K/AKT/mTOR activation and enhanced glycolysis.

Sep 22, 2026

Upload by Jasmine