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Identification of Bone Morphogenetic Protein 7 as a Master Regulator of Gastric Cancer-Associated Cachexia

Mayu Yasuda-Koiwa, Takahiro Shoda, Akiho NishimuraiD, Tadahito YasudaiD, Atsuko YonemuraiD, Kota Muraki, Yuya Okamoto, Takuya TajiriiD, Yanru WangiD, Takatsugu IshimotoiD

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In-depth summary

Claude Sonnet 4.6 · xhigh effort · 8 Nov 2026 · from the full text of version 2 (21 Jul 2026) · CC BY 4.0

In a gastric cancer peritoneal dissemination mouse model, BMP7 knockdown in MKN45 cells attenuated cachexia, and BMP7 acted upstream of GDF11 and GDF15 expression.

Cachexia limits cancer therapy in advanced gastric cancer, and no effective treatment exists because the molecular drivers are poorly understood. This work proposes BMP7 as an upstream regulator of the known mediators GDF11 and GDF15, rather than treating them as independent targets.

Key results

  1. ShownAmong the diffuse-type gastric cancer lines tested, only MKN45 produced cachexia: weight loss, lower grip strength, smaller quadriceps muscle, higher atrophy-marker expression, reduced food intake and less inguinal white fat. Weight loss appeared even when tumor mass was not yet larger.

    Body weight loss only in MKN45-bearing mice (n=4 per group). Grip strength lower vs OCUM-2MD3 (OCUM-2MD3 n = 5, MKN45 n = 6). MuRF1 and Atrogin-1 mRNA higher (n = 3 each). At day 9 tumor mass was not significantly increased vs OCUM-2MD3. · MKN45 possesses particular mechanisms inducing…; Figure legends

  2. ShownA comparison of the cachexia-inducing line MKN45 against NUGC3 and KATOIII in a public microarray dataset gave 13 candidate genes. RT-PCR in five cell lines narrowed these to five, including BMP7, GDF11 and GDF15.

    GSE22183 (37 gastric cancer cell lines) yielded 13 candidates; RT-PCR in five lines confirmed BMP7, GDF15, GDF11, THNSL2 and TNFSF13 as consistently and significantly upregulated in MKN45. · Candidate genes potentially involved in cachexia…; Figure legends

  3. ShownKnocking down BMP7, GDF11 or GDF15 in MKN45 cells attenuated cachexia in vivo without changing tumor mass. Only BMP7 knockdown restored the inguinal white fat index.

    Body weight and grip strength preserved (n=6 mice per group for grip). Group sizes: shBMP7 n=4, shGDF11 n=5, shGDF15 n=6, sh-control n=6. Tumor volumes did not differ. shTHNSL2 and shTNFSF13 matched control (data not shown). · BMP7 induces cachexia by upregulating GDF11 and…; Figure legends

  4. SuggestedBMP7 appears to sit upstream of GDF11 and GDF15 through SMAD1/5 signaling. Direct SMAD binding to their promoters was not demonstrated.

    GDF11 and GDF15 fell in shBMP7 cells and were rescued by 10 ng/ml recombinant BMP7. pSMAD1/5 was reduced and restored likewise. GDF11 or GDF15 knockdown did not change BMP7. Top FIMO SMAD5 motifs: −451 to −442 bp (GDF11), −531 to −522 bp (GDF15). · BMP7 induces cachexia by upregulating GDF11 and…; Recombinant proteins used for in vitro…; In silico promoter motif and ChIP-seq analysis

  5. SuggestedHigh tumor BMP7 expression was associated with poorer overall survival in an institutional advanced gastric cancer cohort and in TCGA diffuse-type advanced disease.

    Kaplan-Meier with log-rank test: significantly poorer overall survival with high BMP7 in 20 advanced gastric cancer patients (IHC). TCGA diffuse-type stage II-IV, median split: high n=30, low n=37. Exact p-values not given in the text. · BMP7 promotes tumor malignancy in advanced GC…; Analysis of The Cancer Genome Atlas and…; Figure legends

Methods, data and reproducibility

Mouse intraperitoneal xenograft models of human gastric cancer lines were phenotyped for cachexia. Candidate genes came from public microarray comparison, then shRNA knockdown, rescue, SMAD1/5 immunoblotting and in silico motif analysis, plus survival analysis.

  • GEMINI microarray expression of gastric cancer cell lines, used to compare MKN45 against NUGC3 and KATOIII · human (cell lines) · n = 37 unique cell lines · GSE22183
  • Male BALB/c nude mice with intraperitoneal injection of NUGC3, OCUM-2MD3 or MKN45 cells (5.0 × 10^6 cells), and MKN45 shRNA lines · mouse · n = n=3 to 9 mice per group, depending on assay
  • Tumor specimens from gastrectomy patients without preoperative treatment, BMP7 immunohistochemistry (Kumamoto University Hospital) · human · n = 20 patients
  • TCGA stomach adenocarcinoma, diffuse-type, stage II-IV, split at median BMP7 mRNA · human · n = high n=30, low n=37
  • Public SMAD1 ChIP-seq (ChIP-Atlas) and JASPAR SMAD5 motif MA1557.1 for GDF11 and GDF15 promoters (hg38) · human · MA1557.1
Methods & tools
GEMINI database, qRT-PCR (SYBR Green, LightCycler 480 System II), shRNA lentiviral knockdown (Sigma TRC clones), IncuCyte S3 live-cell analysis, Western blot (pSMAD1/5), FIMO (MEME Suite), JASPAR SMAD5 motif MA1557.1, ChIP-Atlas, UCSC Genome Browser, Kaplan-Meier with log-rank test, Mann-Whitney U test, SPSS Version 26; Prism Version 9.0.1
Reagents & environment
SPSS Version 26 (IBM) and GraphPad Prism Version 9.0.1 for statistics; promoters defined on hg38; FIMO with JASPAR MA1557.1.
Reproducibility gaps
No code repository is given. Patient IHC data and supplementary tables (Table S1, Table S2) are referenced but not public in the text; only GSE22183 is cited as a data source.
Limitations (5)
  • All animal experiments used male mice only. Cachexia differs by sex, so the BMP7-dependent phenotype may not hold in females. · stated by the authors
  • The transcriptional link is unresolved. Motif scans and public SMAD1 ChIP-seq peaks do not show direct SMAD1/5 binding or promoter activation, so BMP7 may act on GDF11 and GDF15 indirectly. · stated by the authors
  • The interplay between BMP7 and BMP4 remains unclear. OCUM-2MD3 cells have relatively high BMP7 yet are non-cachectic, with elevated BMP4. · stated by the authors
  • Group sizes are small (n=3 to 6 per arm in most assays; 20 patients) and analyzed with Mann-Whitney tests. Effect sizes and exact p-values are mostly not reported, which limits the strength of the inference. · noted in this summary
  • The abstract reports that BMP7 overexpression in NUGC3 induces cachexia and raises GDF11 and GDF15, but the results text shows no data for this experiment. The shTHNSL2 and shTNFSF13 results are also 'data not shown'. · noted in this summary

Read this if you study tumor-derived drivers of cachexia, TGF-β superfamily signaling, or gastric cancer peritoneal metastasis models, and want a BMP7-GDF11/GDF15 hypothesis to evaluate.

Citations
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Abstract

Cachexia is a devastating and multifactorial syndrome characterized by progressive loss of body weight, skeletal muscle wasting, and systemic inflammation, frequently observed in patients with advanced gastric cancer (GC) with peritoneal dissemination. Despite its clinical significance, the molecular mechanisms underlying cancer-associated cachexia remain poorly understood. In this study, comparative transcriptomic analysis using the GEMINI database identified bone morphogenetic protein 7 (BMP7) as a novel candidate cachexia-inducing factor, along with the known cachexia mediators, growth differentiation factor 11 (GDF11) and growth differentiation factor 15 (GDF15). Functional studies demonstrated that BMP7 acts as an upstream regulator that drives cachectic phenotypes by inducing the expression of GDF11 and GDF15. Knockdown of BMP7, GDF11, or GDF15 in the cachexia-inducing GC cell line, MKN45 significantly attenuated weight loss and muscle wasting in vivo. Conversely, overexpression of BMP7 in the non-cachectic GC cell line, NUGC3 induced cachexia and upregulated GDF11 and GDF15 in tumor tissues. Furthermore, clinical analysis revealed that high BMP7 expression in tumor specimens from patients with advanced GC was associated with significantly poorer overall survival. These findings identify BMP7 as a master regulator of cancer-associated cachexia through the induction of GDF11 and GDF15 and suggest its potential as a promising therapeutic target for mitigating cachexia in GC.

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