Clinical utility of a STAT3-regulated miRNA-200 family signature with prognostic potential in early gastric cancer
Published version of a preprint
Abstract
Purpose: The majority of gastric cancer patients are diagnosed with late-stage disease, for which distinct molecular subtypes have been identified that are potentially amenable to targeted therapies. However, there exists no molecular classification system with prognostic power for early-stage gastric cancer (EGC) because the molecular events promoting gastric cancer initiation remain ill-defined. Experimental Design: miRNA microarrays were performed on gastric tissue from the gp130 F/F preclinical EGC mouse model, prior to tumor initiation. Computation prediction algorithms were performed on multiple data sets and independent gastric cancer patient cohorts. Quantitative real-time PCR expression profiling was undertaken in gp130 F/F -based mouse strains and human gastric cancer cells genetically engineered for suppressed activation of the oncogenic latent transcription factor STAT3. Human gastric cancer cells with modulated expression of the miR-200 family member miR-429 were also assessed for their proliferative response. Results: Increased expression of miR-200 family members is associated with both tumor initiation in a STAT3-dependent manner in gp130 F/F mice and EGC (i.e., stage IA) in patient cohorts. Overexpression of miR-429 also elicited contrasting pro- and antiproliferative responses in human gastric cancer cells depending on their cellular histologic subtype. We also identified a miR-200 family-regulated 15-gene signature that integrates multiple key current indic…
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gp130Y757F/Y757F mice show a similar expression pattern of STAT3-dependent miR-200 family members to that of early stage gastric cancer patients.
“Further, the mice show a similar expression pattern of STAT3-dependent miR-200 family members with that of early stage gastric cancer patients (142).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [142]
Cites
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“A "single sample" extension of Geneset Enrichment Analysis (ssGSEA) score (24) was defined an enrichment score that represented the degree of absolute enrichment of the 15 genes targeted by the miR-200 family in each sample within a given data set (25).”
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BackgroundmiR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response
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“Therefore, the epithelial phenotype of MKN28 cells aligns with cell proliferation and clonal growth, which is reflective of early-stage disease, while the mesenchymal morphology of MKN1 cells favors metastasis during late-stage disease progression (31, 32).”
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“In addition, the miR-200 family has been identified as a key regulatory network that defines a mesenchymal gastric cancer subtype associated with poor survival (13, 14).”
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“Another keyfindingof our studywas thatmiR-429 expression is positively regulated by IL11/STAT3 signaling, a key driver of gastric cancer (15, 35).”
BackgroundGenome‐wide identification of miR‐200 targets reveals a regulatory network controlling cell invasion
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BackgroundSelf-citationApplication of minimally invasive treatment for early gastric cancer
Hyung, W., Cheong, J., Kim, J., Chen, J., Choi, S.-H., & Noh, S. (2004) · Journal of Surgical Oncology · doi:10.1002/jso.20018 · Cited by 119 · cited 1× · see citing works
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“In addition, the miR-200 family has been identified as a key regulatory network that defines a mesenchymal gastric cancer subtype associated with poor survival (13, 14).”
BackgroundResultHan, C., Liu, Y.-H., Wan, G., Choi, H., Zhao, L.-Q., Ivan, C., He, X.-M., Sood, A., Zhang, X.-N., & Lu, X.-B. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.058 · Cited by 102 · cited 1× · see citing works
“In this respect,we cannot exclude the possibility that STAT3 may indirectly regulate miR-200 family members via its transcriptional regulation of miRNA processors, such as DDX1 (46), which in turn regulate miR-200 family maturation.”
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“However, themiR-200 family has been assigned oncogenic and tumorsuppressive roles in diverse cancers, as evidenced by their upregulation in lung, ovarian, and esophageal cancers, and conversely downregulation in hepatocellular and gastric cancers (39, 40).”
BackgroundThe use of miRNA microarrays for the analysis of cancer samples with global miRNA decrease
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“Cellular functional and luciferase reporter assays Cell proliferationwas assessedwith the ClickIT EdUMicroplate Assay (Molecular Probes), and cell viability was measured using the Cell-Glo ATP assay (26).”
MethodSelf-citationNetwork-Based Approaches to Understand the Roles of miR-200 and Other microRNAs in Cancer.
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“Indeed, the steady decline inmiR-200 familymembers' expression from stage IB onwards toward themore advanced disease stages is consistent with their tumor suppressor functions (21, 42).”
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“, colorectal, lung), family members such as miR-429 are differentially expressed and display contrasting anti- and protumorigenic roles (39, 41), suggesting that at least in some cancers, the role of the miR-200 family is also stage-dependent.”
BackgroundEarly Gastric Cancer: Current Advances of Endoscopic Diagnosis and Treatment
Zhu, L.-L., Qin, J.-Y., Wang, J., Guo, T.-J., Wang, Z., & Yang, J.-L. (2016) · Gastroenterology Research and Practice · doi:10.1155/2016/9638041 · Cited by 43
Expression and clinical significance of the microRNA-200 family in gastric cancer.
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“It is also worth considering our findings with recent studies showing that impaired expression of miR-200 family members, predominantly miR-200b and miR-200c, is a marker of poor prognosis for gastric cancer patients (13, 14, 44), which concur with our data revealing that high miR-200 family expression is a favorable…”
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“Indeed, such a scenario has been reported in a subset of gastric cancer patients suffering relapse and metastasis despite their tumors being clinically graded as "early" (4, 5).”
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Self-citationThe Japanese Viewpoint on the Histopathology of Early Gastric Cancer.
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“Indeed, such a scenario has been reported in a subset of gastric cancer patients suffering relapse and metastasis despite their tumors being clinically graded as "early" (4, 5).”
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IL-6 in inflammation, autoimmunity and cancer
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“An increased expression of miR-200 family members is associated with both tumor initiation in STAT3-dependent murine gastric cancer and early-stage gastric cancer in patient cohorts (142).”
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“miRNAs play vital roles in various pathological processes such as cell proliferation, cell stemness, and the aggressiveness of GC cells (21, 22).”
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Complete loss of miR-200 family induces EMT associated cellular senescence in gastric cancer
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Self-citationLandscape of Innovative Methods for Early Diagnosis of Gastric Cancer: A Systematic Review
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“Yu et al. discovered that members of the miR-200 family increased in EGC [95] and aided in the early detection of GC.”
BackgroundBiomarkers of gastric cancer: current advancement
Jiang, T., Mei, L., Yang, X., Sun, T., Wang, Z.-D., & Ji, Y.-Y. (2022) · Heliyon · doi:10.1016/j.heliyon.2022.e10899 · Cited by 32 · see citing works
“found that miR-200 family members increased in early GC [78].”
BackgroundGao, C., Cai, X. M., Fu, Q., Yang, N., Song, L., Su, B., Tan, F., Liu, B., & Li, C. (2019) · Marine Biotechnology · doi:10.1007/s10126-019-09903-z · Cited by 35 · see citing works
Balic, J. J., Garama, D. J., Saad, M. I., Yu, L., West, A. C., West, A. J., Livis, T., Bhathal, P. S., Gough, D. J., & Jenkins, B. J. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0974 · Cited by 33 · see citing works
Self-citationPeng, J., Liu, F., Zheng, H., Wu, Q., & Liu, S.-X. (2020) · Cell Cycle · doi:10.1080/15384101.2020.1864128 · Cited by 28 · see citing works
Rojas-Sánchez, G., Cotzomi-Ortega, I., Pazos-Salazar, N. G., Reyes‐Leyva, J., & Maycotte, P. (2019) · Biology · doi:10.3390/biology8040071 · Cited by 32 · see citing works
Recent advances of miRNAs in the development and clinical application of gastric cancer
Wu, S., Wu, Q., & Shi, Y.-Q. (2020) · Chinese Medical Journal · doi:10.1097/cm9.0000000000000921 · Cited by 26 · see citing works
Liu, L., Tian, Y., Mao, G., Zhang, Y.-G., & Han, L. (2019) · Cellular Signalling · doi:10.1016/j.cellsig.2019.109352 · Cited by 25
miR-632 promotes gastric cancer progression by accelerating angiogenesis in a TFF1-dependent manner
Shi, Y., Huang, X., Chen, G.-B., Wang, Y., Liu, Y.-S., Xu, W., Tang, S.-H., Guleng, B., Liu, J.-J., & Ren, J.-L. (2019) · BMC Cancer · doi:10.1186/s12885-018-5247-z · Cited by 22 · see citing works
“diagnosis provides predictive power to inform early GC patients and has the potential to be applied in endoscopic treatment [14].”
Self-citationGastric cancer: An epigenetic view
Tang, S., Zhou, P., Meng, Y., Zeng, F.-R., & Deng, G.-T. (2022) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v14.i1.90 · Cited by 20 · see citing works
PLXNC1 Enhances Carcinogenesis Through Transcriptional Activation of IL6ST in Gastric Cancer
Chen, J., Liu, H., Chen, J., Sun, B., Wu, J., & Du, C. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00033 · Cited by 21 · see citing works
“as GP130) controls the IL-6/STAT3 signaling pathway and accelerates gastric tumorigenesis (14, 15).”
BackgroundIzraely, S., Ben‐Menachem, S., Malka, S., Sagi‐Assif, O., Bustos, M. A., Adir, O., Meshel, T., Chelladurai, M., Ryu, S., Ramos, R. I., et al. (2023) · Cells · doi:10.3390/cells12111513 · Cited by 15 · see citing works
“Factors secreted by four MBM cell lines uniformly altered the expression of five genes in microglia including the STAT3 target gene SOCS3 [70].”
BackgroundFang, R., Lu, Q., & Xu, B. (2021) · Molecular Medicine Reports · doi:10.3892/mmr.2021.12092 · Cited by 15
Differential expression and role of miR-200 family in multiple tumors.
Wen, B., Zhu, R., Jin, H., & Zhao, K. (2021) · Analytical Biochemistry · doi:10.1016/j.ab.2021.114243 · Cited by 13 · see citing works
Expression of miR-664 and miR-184 on proliferation, apoptosis and migration of osteosarcoma cells
Tao, P., Feng, J., Li, Q., Liu, W., Yang, L., Zhao, X., Ni, H., & Xia, P. (2018) · Oncology Letters · doi:10.3892/ol.2018.9739 · Cited by 9 · see citing works
“In recent years, there have been many studies showing that the expression of miRNA is closely correlated with the clinical features and prognosis of tumors, including lung cancer (17), gastric cancer (18) and breast cancer (19).”
BackgroundArtificial intelligence-guided discovery of gastric cancer continuum
Vo, D., Ghosh, P., & Sahoo, D. (2022) · bioRxiv · doi:10.1007/s10120-022-01360-3 · Cited by 7
“We analyzed 38 mouse models [24-41] from 20 NCBI GEO datasets using C#11-2-4-14 and C#7-1314 (see Online Resource 2 for a list of GSE IDs; Fig.”
MethodKrstić, M., Stojanović, N., Stojnev, S., Radenković, G., Cukuranovic-Kokoris, J., Mladenovic, B., & Janković-Veličković, L. (2019) · Medicina · doi:10.3390/medicina55060300 · Cited by 7
“Our results suggest that STAT3 expression is significantly associated with poor tumor histological differentiation and the presence of distant metastases, the two features of GC previously shown to be tightly related to pronounced EMT [31].”
BackgroundInfluentialQian, L., Wang, L., Chen, H., Wang, S., Hou, Y., Xu, L., Xia, Y.-B., Xu, M., & Huang, X. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1511247 · Cited by 6 · see citing works
Yan, W., Chen, Y.-Q., Hu, G., Shi, T.-G., Liu, X.-Y., Li, J.-T., Sun, L.-Q., Qian, F., & Chen, W. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04010-z · Cited by 4
“Previous studies have demonstrated that down-regulation of miR-200 family members promotes GC progression in vitro in GC cell lines [38–41] and characterize sub-types of GC with poor-prognosis [42].”
BackgroundResultSelf-citationThe role of microRNAs in gastritis, intestinal metaplasia, and gastric cancer: a narrative review
Gao, Z., Fu, K.-Y., Li, P., Fang, Z., Liu, J., & Shang, L. (2025) · Translational Cancer Research · doi:10.21037/tcr-2025-1-2642 · Cited by 3
“Yu et al. found that STAT3-regulated miR-200 family-associated genes hold superior predictive value for overall survival in GC patients (148).”
Bahadoran, E., Babaei, A., Ranji, R., Badameh, P., Sabzi, S., Rahmani, B., & Ebadi, H. (2025) · Critical reviews in oncology/hematology · doi:10.1016/j.critrevonc.2025.104795 · Cited by 3
Mouhmed, E. A., Farghali, A., Tawab, S. A.-E., Mahmoud, R. K., & Ewees, M. G. E.-D. (2026) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2026.108441 · Cited by 1
The role of inflammation in gastric tumorigenesis
Oshima, H., Ju, X.-L., Echizen, K., Han, T.-S., & Oshima, M. (2021) · Research and Clinical Applications of Targeting Gastric Neoplasms · doi:10.1016/b978-0-323-85563-1.00012-5 · Cited by 1
Self-citationŠkrha, P., Hořínek, A., Hajer, J., Potočková, J., Frič, P., Bures, J., Anděl, M., & Škrha, J. (2025) · Physiological Research · doi:10.33549/physiolres.935586
“…properties and worse prognosis were found in transformed mammary epithelial cells connected with overexpression of miR-200 family [50], as well as in early gastric cancer [51], oral squamous cell cancer [52], colorectal cancer [53], ovarian cancer [54] or in non-small cell lung cancer [55].”
FAM117A and PIGU regulate the trilogy of gastric carcinogenesis
Chen, N., Wen, Y., Liu, Q., Du, J., Yao, D., Zhao, M., Guo, C., Wang, T., Ma, J., Tang, J., et al. (2025) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2025.08.036
“Numerous studies have demonstrated that miRNAs and lncRNAs are implicated in key cellular processes of gastric cancer, including differentiation, proliferation, apoptosis, migration, invasion, and metastasis of gastric cancer cells [12,13].”
Huang, X., Liu, F.-J., Guan, H., Jiang, Z., Wei, P., Luo, Y.-F., & Jia, Q.-H. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10238
“Finally, the tissue was examined pathologically for residual GC tissue (5,6).”
Background
- Authors
- Yu, L., Wu, D., Gao, H., Balic, J. J., Tsykin, A., Han, T.-S., Liu, Y. D., Kennedy, C. L., Li, J. K., Mao, J. Q., Tan, P., Oshima, M., Goodall, G. J., & Jenkins, B. J.
- Affiliations
- Hudson Institute of Medical Research (AU)
- University of North Carolina at Chapel Hill (US)
- South Australia Pathology (AU)
- Kanazawa University (JP)
- 1Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
- Shanghai Jiao Tong University (CN)
- National University of Singapore (SG)
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2018-03-14
- Volume
- 24
- Issue
- 6
- Pages
- 1459-1472
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2782670265
- Cited by
- 50
- References
- 48
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 1 · 2023: 5 · 2022: 3 · 2021: 9 · 2020: 11 · 2019: 8 · 2018: 6
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- Association for International Cancer Research (AICR) (11-0017)
- Cancer Council Victoria (1003597)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- early gastric cancer, STAT3, miR-200 family, miR-429, prognostic gene signature, tumor initiation, overall survival prediction, histological subtypes
- MeSH terms
- Animals, Humans, Neoplasm Staging, Prognosis, Stomach Neoplasms, Cohort Studies, Gene Expression Regulation, Neoplastic, Mice, Knockout, Gene Expression Profiling, MicroRNAs, Cell Line, Tumor, STAT3 Transcription Factor, Cytokine Receptor gp130, Kaplan-Meier Estimate, HEK293 Cells
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