Intracellular MUC20 variant 2 maintains mitochondrial calcium homeostasis and enhances drug resistance in gastric cancer

Fu, Lingfeng; Yonemura, Atsuko; Yasuda-Yoshihara, Noriko; Umemoto, Terumasa; Zhang, Jun; Yasuda, Tadahito; Uchihara, Tomoyuki; Akiyama, Takahiko; Kitamura, Fumimasa; Yamashita, Kohei; Okamoto, Yuka; Bu, Luke; Feng, Wen; Hu, Xichen; Liu, Yang; Ajani, Jaffer A.; Tan, Patrick; Baba, Hideo; Ishimoto, Takatsugu

doi:10.1007/s10120-022-01283-z

Cited by 21 publications

(20 citation statements)

References 45 publications

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“…The Kaplan–Meier plotter survival tool evaluated the correlation between more than 30 thousand gene expression and survival in 21 tumors, including breast cancer, lung cancer, GC, etc. Some of the survival data were derived from TCGA database and were also widely used in the basic research of cancer 28–31 . In the present study, we identified a novel GC‐related lncRNA LGALS8‐AS1 through TCGA database combined with the Kaplan–Meier plotter survival tool.…”

Section: Discussionmentioning

confidence: 98%

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Long non‐coding RNA LGALS8‐AS1 facilitates PLAGL2‐mediated malignant phenotypes in gastric cancer

Wang

Shen

Xiao

et al. 2023

The Journal of Gene Medicine

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Background Great progress has been made in studying the function of long non‐coding RNA (lncRNA) in various tumors, including gastric cancer (GC). However, there are still numerous lncRNAs that have not yet been studied and explored for their roles in GC, and their important functions need to be further revealed. Methods Through analyzing The Cancer Genome Atlas (TCGA) database combined with bioinformatics survival tools, a novel GC‐related lncRNA LGALS8‐AS1 was identified. A quantitative real‐time polymerase chain reaction and a series of in vitro or in vivo cell functional experiments were performed to determine the expression and the role of LGALS8‐AS1/miR‐138‐5p/PLAGL2 in GC. Results LGALS8‐AS1 was remarkably upregulated and correlated with the unfavorable prognosis in GC. Higher expression of LGALS8‐AS1 was positively associated with higher lymph node metastasis rate, as well as larger tumor size. In addition, a series of cell functional experiments revealed that LGALS8‐AS1 could facilitate GC cell proliferation, migration and metastasis in vitro or in vivo. A deeper mechanism exploration revealed that LGALS8‐AS1 could function as the miR‐138‐5p molecular sponge and upregulate the PLAGL2 expression, thereby promoting the cell proliferation, migration and metastasis in GC. Conclusions In brief, we revealed the tumor promoting role of the LGALS8‐AS1/miR‐138‐5p/PLAGL2 molecular signaling axis in GC, and our findings provide enlightenment for further understanding of the mechanism of tumorigenesis and development of GC, making LGALS8‐AS1 a possible new diagnostic or therapeutic target for GC.

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Section: Discussionmentioning

confidence: 98%

“…Some of the survival data were derived from TCGA database and were also widely used in the basic research of cancer. [28][29][30][31] In the present study, we identified a novel GC-related lncRNA LGALS8-AS1 through TCGA database combined with the Kaplan-Meier plotter survival tool.…”

Section: Discussionmentioning

confidence: 99%

Long non‐coding RNA LGALS8‐AS1 facilitates PLAGL2‐mediated malignant phenotypes in gastric cancer

Wang

Shen

Xiao

et al. 2023

The Journal of Gene Medicine

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“…MUC20 variant 2 is specifically expressed in gastric cancer. It can maintain mitochondrial calcium homeostasis and increase drug resistance by inhibiting apoptosis through suppression of the AKT/mTOR pathway 25 . MUC20 can activate the HGF/MET pathway in pancreatic cancer cells and promote cell proliferation, migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

“…MUC20 can activate the HGF/MET pathway in pancreatic cancer cells and promote cell proliferation, migration and invasion. In contrast, silencing MUC20 attenuates the malignant phenotype of pancreatic cancer cells and induces their apoptosis 25 . MUC20 interacts with HER2 and regulates its downstream signaling, including signaling through the PI3K/AKT/mTOR pathway.…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel promotes mTOR signaling‐mediated apoptosis in esophageal cancer cells by targeting MUC20

Li,

Feng,

Han

et al. 2023

Thoracic Cancer

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BackgroundThe aim of this study was to analyze the effect of paclitaxel on the apoptosis of esophageal cancer cells in relation to MUC20.MethodsRT‐qPCR analysis, a CCK‐8 assay, western blotting, and flow cytometry were used to analyze the anticancer effects of paclitaxel treatment or OE‐MUC20 in vitro and in vivo.ResultsThe in vitro results showed that paclitaxel significantly induced MUC20 upregulation and that paclitaxel treatment or OE‐MUC20 significantly decreased esophageal cancer cell viability and increased mTOR signaling activation and apoptosis. In addition, PKM2, a key downstream molecule of mTOR signaling, similarly showed significant upregulation after paclitaxel treatment in cells with OE‐MUC20, and its expression was attenuated after treatment with mTOR inhibitors. In a nude mouse model, tumor growth was slow in the OE‐MUC20 group and accelerated after inhibition of mTOR signaling.ConclusionThese data suggest that MUC20 is an important target of paclitaxel in esophageal cancer and promotes apoptosis through activation of mTOR signaling.

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“…Pyroptotic resistance can inhibit antitumor immunity and promote the development of multiple types of cancer [10]. Tumor cell resistance to pyroptosis can induce chemotherapy resistance, while the promotion of cell pyroptosis can enhance the clinical effect of anticancer therapies in patients with tumors [11]. Platinum is one of the most commonly used antitumor chemotherapeutic drugs for the treatment of gynecologic cancers [12].However, platinum resistance is a common phenomenon and results in cancer recurrence and metastasis, both of which remain major challenges in clinical practice.…”

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confidence: 99%

ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer

Mao

et al. 2023

Preprint

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Background Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptosis pathway and glycolytic metabolism. Methods The protein interaction between ERRα and HIF-1α was verified by Co-immunoprecipitation. The transcriptional binding sites of ERRα and NLRP3 were confirmed by dual-luciferase reporter assay. Flow cytometry, transmission electron microscopy, and extracellular acidification rate analysis were performed to investigate the effect of ERRα on the pyroptosis pathway and glycolytic metabolism. This experiments were further confirmed in EC-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis genes was analyzed by the The Cancer Genome Atlas database. Results Triggered by a hypoxic microenvironment, highly-expressed-ERRα could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in cancer cells resistant to cisplatin. Moreover, ERRα activated pyruvate kinase M2 (PKM2), a glycolytic rate-limiting enzyme, to bridge glycolytic metabolism and pyroptosis in endometrial cancer (EC). This phenomenon was further confirmed in EC-derived organoids and nude mice. The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in the progression of EC. Conclusions ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells.

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Intracellular MUC20 variant 2 maintains mitochondrial calcium homeostasis and enhances drug resistance in gastric cancer

Cited by 21 publications

References 45 publications

Long non‐coding RNA LGALS8‐AS1 facilitates PLAGL2‐mediated malignant phenotypes in gastric cancer

Long non‐coding RNA LGALS8‐AS1 facilitates PLAGL2‐mediated malignant phenotypes in gastric cancer

Paclitaxel promotes mTOR signaling‐mediated apoptosis in esophageal cancer cells by targeting MUC20

ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer

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