image: (A) Overexpression (A1) or knockdown (A2) of SERHL in transfected AGS and MKN-74 cell lines were analyzed by quantitative PCR. ∗∗∗∗P < 0.001 for Control vs. SERHL; ∗∗∗P < 0.01 and ∗∗∗∗P < 0.001 for dCas9-control vs. dCas9-SERHL. (B1/2) Transwell assays revealed the effects of SERHL on the migration of AGS and MKN-74 cells. ∗∗∗∗P < 0.001 for Control vs. SERHL; ∗∗∗P < 0.01 and ∗∗∗∗P < 0.001 for dCas9-control vs. dCas9-SERHL. Data represent mean ± standard deviation. (C) Gastric cancer cell motility was detected using the wound healing assay, with bar graphs on the right quantifying their mobility. ∗∗P < 0.05, ∗∗∗P < 0.01, and ∗∗∗∗P < 0.001. (D1/2) White light and fluorescence images showed tumor metastases forming in the lungs of nude mice after tail vein injection (D1). Quantification results of the lung metastatic foci area were presented by scatter plots (D2). ∗∗∗∗P < 0.001. (E1/2) Typical pictures of the hematoxylin-eosin and immunohistochemical staining in Vector and SERHL groups of nude mice lungs (E1). The immunoreactive score (IRS) was compared between different groups (E2). ∗∗∗P < 0.01. Scale bars, 100 μm. (F, G) The analysis of AKT/mTOR signaling pathway in SERHL overexpression (F) or knockdown (G) gastric cancer cells. AKT pathway inhibitor LY294002 was used to inhibit AKT/mTOR activation.
Credit: Linjie Hong, Siyang Peng, Yidong Chen, Yanci Xie, Yuting Lei, Jieke Wu, Xiaodong Huang, Xiangyang Wei, Ping Yang, Jieming Zhang, Qiong Yang, Weimei Tang, Xiaosheng Wu, Ying Peng, Zhizhao Lin, AiminLi, Side Liu, Jiaying Li, Weiyu Dai, Jide Wang
Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide, with metastasis accounting for the majority of patient deaths. Although advances in molecular profiling have improved our understanding of gastric tumorigenesis, the mechanisms driving invasion and metastatic spread remain incompletely understood. Pseudogenes, once considered nonfunctional genomic relics, are increasingly recognized as important regulators of cancer biology. However, the functions of many pseudogenes in gastric cancer progression have yet to be defined.
In a recent study published in Genes & Diseases, researchers from Southern Medical University, Fujian Medical University and Guangzhou Medical University identified SERHL, a unitary pseudogene, as a previously unrecognized tumor suppressor in gastric cancer. Combining analyses of patient specimens, transcriptomic profiling, molecular biology techniques, and mouse metastasis models, the investigators uncovered a SERHL–KLF16–PLCB1/PRKCA signaling pathway that restrains tumor invasion by suppressing phosphatidylinositol (PI) signaling and downstream AKT/mTOR activation.
The researchers first demonstrated that SERHL expression was significantly reduced in gastric cancer tissues and cell lines compared with normal gastric epithelium. Low SERHL expression correlated with larger tumor size, advanced TNM stage, deeper local invasion, and lymph node metastasis, indicating a close association with aggressive disease. Cellular localization studies further showed that SERHL is predominantly localized within the nucleus, suggesting a role in transcriptional regulation.
Functional experiments revealed that restoring SERHL expression markedly inhibited gastric cancer cell migration, invasion, and metastatic potential, whereas SERHL depletion promoted these malignant phenotypes. Mechanistic analyses identified the transcription factor KLF16 as a direct downstream target of SERHL. The study showed that SERHL suppresses KLF16 expression, preventing KLF16 from transcriptionally activating PLCB1 and PRKCA, two key components of the phosphatidylinositol signaling pathway. DNA pull-down, chromatin immunoprecipitation, and luciferase reporter assays confirmed direct binding of KLF16 to the promoters of both genes, establishing PLCB1 and PRKCA as bona fide transcriptional targets of KLF16.
Further experiments demonstrated that activation of the KLF16–PLCB1/PRKCA axis stimulated AKT/mTOR signaling, thereby enhancing gastric cancer cell migration and invasion. Silencing either PLCB1 or PRKCA effectively abolished the prometastatic effects of KLF16 overexpression, while restoring SERHL expression suppressed lung metastasis in mouse models. Analyses of patient tissues further revealed inverse correlations between SERHL and KLF16, PLCB1, and PRKCA expression, supporting the clinical relevance of this regulatory pathway.
Overall, this study identifies SERHL as a novel pseudogene-derived tumor suppressor that restrains gastric cancer metastasis by inhibiting the KLF16–PLCB1/PRKCA–AKT/mTOR signaling cascade. By uncovering an unexpected role for a pseudogene in regulating phosphatidylinositol signaling and metastatic progression, the findings broaden current understanding of gastric cancer biology and highlight the SERHL signaling axis as a promising target for future therapeutic strategies aimed at limiting metastatic disease.
Reference
Title of Original Paper: SERHL regulates invasion and metastasis through KLF16-PLCB1/PRKCA signaling in gastric cancer cells
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101884
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