TMEM65 promotes gastric tumorigenesis by targeting YWHAZ to activate PI3K-Akt-mTOR pathway and is a therapeutic target
© 2024. The Author(s)..
Copy number alterations are crucial for the development of gastric cancer (GC). Here, we identified Transmembrane Protein 65 (TMEM65) amplification by genomic hybridization microarray to profile copy-number variations in GC. TMEM65 mRNA level was significantly up-regulated in GC compared to adjacent normal tissues, and was positively associated with TMEM65 amplification. High TMEM65 expression or DNA copy number predicts poor prognosis (P < 0.05) in GC. Furtherly, GC patients with TMEM65 amplification (n = 129) or overexpression (n = 78) significantly associated with shortened survival. Ectopic expression of TMEM65 significantly promoted cell proliferation, cell cycle progression and cell migration/invasion ability, but inhibited apoptosis (all P < 0.05). Conversely, silencing of TMEM65 in GC cells showed opposite abilities on cell function in vitro and suppressed tumor growth and lung metastasis in vivo (all P < 0.01). Moreover, TMEM65 depletion by VNP-encapsulated TMEM65-siRNA significantly suppressed tumor growth in subcutaneous xenograft model. Mechanistically, TMEM65 exerted oncogenic effects through activating PI3K-Akt-mTOR signaling pathway, as evidenced of increased expression of key regulators (p-Akt, p-GSK-3β, p-mTOR) by Western blot. YWHAZ (Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase) was identified as a direct downstream effector of TMEM65. Direct binding of TMEM65 with YWHAZ in the cytoplasm inhibited ubiquitin-mediated degradation of YWHAZ. Moreover, oncogenic effect of TMEM65 was partly dependent on YWHAZ. In conclusion, TMEM65 promotes gastric tumorigenesis by activating PI3K-Akt-mTOR signaling via cooperating with YWHAZ. TMEM65 overexpression may serve as an independent new biomarker and is a therapeutic target in GC.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
|---|---|
| Enthalten in: |
Oncogene - 43(2024), 13 vom: 27. März, Seite 931-943 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Shi, Lingxue [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 25.03.2024 Date Revised 27.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41388-024-02959-9 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM368309851 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM368309851 | ||
| 003 | DE-627 | ||
| 005 | 20240327235757.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240211s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41388-024-02959-9 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1351.xml |
| 035 | |a (DE-627)NLM368309851 | ||
| 035 | |a (NLM)38341472 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Shi, Lingxue |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a TMEM65 promotes gastric tumorigenesis by targeting YWHAZ to activate PI3K-Akt-mTOR pathway and is a therapeutic target |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.03.2024 | ||
| 500 | |a Date Revised 27.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a Copy number alterations are crucial for the development of gastric cancer (GC). Here, we identified Transmembrane Protein 65 (TMEM65) amplification by genomic hybridization microarray to profile copy-number variations in GC. TMEM65 mRNA level was significantly up-regulated in GC compared to adjacent normal tissues, and was positively associated with TMEM65 amplification. High TMEM65 expression or DNA copy number predicts poor prognosis (P < 0.05) in GC. Furtherly, GC patients with TMEM65 amplification (n = 129) or overexpression (n = 78) significantly associated with shortened survival. Ectopic expression of TMEM65 significantly promoted cell proliferation, cell cycle progression and cell migration/invasion ability, but inhibited apoptosis (all P < 0.05). Conversely, silencing of TMEM65 in GC cells showed opposite abilities on cell function in vitro and suppressed tumor growth and lung metastasis in vivo (all P < 0.01). Moreover, TMEM65 depletion by VNP-encapsulated TMEM65-siRNA significantly suppressed tumor growth in subcutaneous xenograft model. Mechanistically, TMEM65 exerted oncogenic effects through activating PI3K-Akt-mTOR signaling pathway, as evidenced of increased expression of key regulators (p-Akt, p-GSK-3β, p-mTOR) by Western blot. YWHAZ (Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase) was identified as a direct downstream effector of TMEM65. Direct binding of TMEM65 with YWHAZ in the cytoplasm inhibited ubiquitin-mediated degradation of YWHAZ. Moreover, oncogenic effect of TMEM65 was partly dependent on YWHAZ. In conclusion, TMEM65 promotes gastric tumorigenesis by activating PI3K-Akt-mTOR signaling via cooperating with YWHAZ. TMEM65 overexpression may serve as an independent new biomarker and is a therapeutic target in GC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a 14-3-3 Proteins |2 NLM | |
| 650 | 7 | |a Glycogen Synthase Kinase 3 beta |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Phosphatidylinositol 3-Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.1.- |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a TOR Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a YWHAZ protein, human |2 NLM | |
| 650 | 7 | |a TMEM65 protein, human |2 NLM | |
| 700 | 1 | |a Wang, Xiaohong |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Shang |e verfasserin |4 aut | |
| 700 | 1 | |a Gou, Hongyan |e verfasserin |4 aut | |
| 700 | 1 | |a Shang, Haiyun |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Xiaojia |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Chunxian |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lihong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Zengren |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Weifang |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Jun |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Oncogene |d 1990 |g 43(2024), 13 vom: 27. März, Seite 931-943 |w (DE-627)NLM012595683 |x 1476-5594 |7 nnns |
| 773 | 1 | 8 | |g volume:43 |g year:2024 |g number:13 |g day:27 |g month:03 |g pages:931-943 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41388-024-02959-9 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 43 |j 2024 |e 13 |b 27 |c 03 |h 931-943 | ||