bims-meluca 2021-05-30 papers

BMC Cancer. 2021 May 27. 21(1): 626

A glycolysis-based three-gene signature predicts survival in patients with lung squamous cell carcinoma.

Guichuan Huang, Jing Zhang, Ling Gong, Yi Huang, Daishun Liu.

BACKGROUND: Lung cancer is one of the most lethal and most prevalent malignant tumors worldwide, and lung squamous cell carcinoma (LUSC) is one of the major histological subtypes. Although numerous biomarkers have been found to be associated with prognosis in LUSC, the prediction effect of a single gene biomarker is insufficient, especially for glycolysis-related genes. Therefore, we aimed to develop a novel glycolysis-related gene signature to predict survival in patients with LUSC.
METHODS: The mRNA expression files and LUSC clinical information were obtained from The Cancer Genome Atlas (TCGA) dataset.
RESULTS: Based on Gene Set Enrichment Analysis (GSEA), we found 5 glycolysis-related gene sets that were significantly enriched in LUSC tissues. Univariate and multivariate Cox proportional regression models were performed to choose prognostic-related gene signatures. Based on a Cox proportional regression model, a risk score for a three-gene signature (HKDC1, ALDH7A1, and MDH1) was established to divide patients into high-risk and low-risk subgroups. Multivariate Cox regression analysis indicated that the risk score for this three-gene signature can be used as an independent prognostic indicator in LUSC. Additionally, based on the cBioPortal database, the rate of genomic alterations in the HKDC1, ALDH7A1, and MDH1 genes were 1.9, 1.1, and 5% in LUSC patients, respectively.
CONCLUSION: A glycolysis-based three-gene signature could serve as a novel biomarker in predicting the prognosis of patients with LUSC and it also provides additional gene targets that can be used to cure LUSC patients.

Keywords: Gene signature; Glycolysis; Lung cancer; Prognosis

DOI: https://doi.org/10.1186/s12885-021-08360-z

Cancer Sci. 2021 May 25.

An AKT/PRMT5/SREBP1 axis in lung adenocarcinoma regulates de novo lipogenesis and tumor growth.

Liu Liu, Hui Yan, Maomei Ruan, Hao Yang, Lihua Wang, Bei Lei, Xiaoyan Sun, Cheng Chang, Gang Huang, Wenhui Xie.

Protein kinase B (AKT) hyperactivation and de novo lipogenesis are both common in tumor progression. Sterol regulatory element-binding protein 1 (SREBP1) is the master regulator for tumor lipid metabolism, and protein arginine methyltransferase 5 (PRMT5) is an enzyme that can catalyze symmetric dimethyl arginine (SDMA) modification of the mature form of SREBP1 (mSREBP1) to induce its hyperactivation. Here, we report that SDMA-modified mSREBP1 (mSREBP1-SDMA) was overexpressed and correlated with ser473-phosphorylated AKT (AKT-473P) expression and poor patient outcomes in human lung adenocarcinomas. Further, patients with AKT-473P and mSREBP1-SDMA co-expression showed the worst prognosis. Mechanistic investigation revealed that AKT activation upregulated SREBP1 at both the transcriptional and post-translational levels, whereas PRMT5 knockdown reversed AKT signaling-mediated mSREBP1 ubiquitin-proteasome pathway stabilization at the post-translational level. Meanwhile, AKT activation promoted nuclear PRMT5 to the cytoplasm without changing total PRMT5 expression, and the transported cytoplasmic PRMT5 (cPRMT5) induced by AKT activation showed a strong mSREBP1-binding ability. IHC assay demonstrated that AKT-473P and mSREBP1-SDMA were positively correlated with cPRMT5 in lung adenocarcinomas, and high cPRMT5 levels in tumors were associated with poor patient outcomes. Additionally, PRMT5 knockdown reversed AKT activation-induced lipid synthesis and growth advantage of lung adenocarcinoma cells both in vitro and in vivo. Finally, we defined an AKT/PRMT5/SREBP1 axis involved in de novo lipogenesis and the growth of lung cancer. Our data also support that cPRMT5 is a potential therapeutic target for hyperactive AKT-driven lung adenocarcinoma. Supporting Information.

Keywords: AKT; PRMT5; SREBP1; de novo lipogenesis; lung adenocarcinoma

DOI: https://doi.org/10.1111/cas.14988

Cell Death Differ. 2021 May 26.

AMPKα loss promotes KRAS-mediated lung tumorigenesis.

Manuela La Montagna, Lei Shi, Peter Magee, Sudhakar Sahoo, Matteo Fassan, Michela Garofalo.

AMP-activated protein kinase (AMPK) is a critical sensor of energy status that coordinates cell growth with energy balance. In non-small cell lung cancer (NSCLC) the role of AMPKα is controversial and its contribution to lung carcinogenesis is not well-defined. Furthermore, it remains largely unknown whether long non-coding RNAs (lncRNAs) are involved in the regulation of AMPK-mediated pathways. Here, we found that loss of AMPKα in combination with activation of mutant KRASG12D increased lung tumour burden and reduced survival in KrasLSLG12D/+/AMPKαfl/fl mice. In agreement, functional in vitro studies revealed that AMPKα silencing increased growth and migration of NSCLC cells. In addition, we identified an AMPKα-modulated lncRNA, KIMAT1 (ENSG00000228709), which in turn regulates AMPKα activation by stabilizing the lactate dehydrogenase B (LDHB). Collectively, our study indicates that AMPKα loss promotes KRAS-mediated lung tumorigenesis and proposes a novel KRAS/KIMAT1/LDHB/AMPKα axis that could be exploited for therapeutic purposes.

DOI: https://doi.org/10.1038/s41418-021-00777-0

Life Sci. 2021 May 24. pii: S0024-3205(21)00635-4. [Epub ahead of print] 119649

Therapeutic potential of AMPK signaling targeting in lung cancer: Advances, challenges and future prospects.

Milad Ashrafizadeh, Sepideh Mirzaei, Kiavash Hushmandi, Vahid Rahmanian, Amirhossein Zabolian, Mehdi Raei, Mahdi Vasheghani Farahani, Mohammad Ali Sheikh Beig Goharrizi, Haroon Khan, Ali Zarrabi, Saeed Samarghandian.

Lung cancer (LC) is a leading cause of death worldwide with high mortality and morbidity. A wide variety of risk factors are considered for LC development such as smoking, air pollution and family history. It appears that genetic and epigenetic factors are also potential players in LC development and progression. AMP-activated protein kinase (AMPK) is a signaling pathway with vital function in inducing energy balance and homeostasis. An increase in AMP:ATP and ADP:ATP ratio leads to activation of AMPK signaling by upstream mediators such as LKB1 and CamKK. Dysregulation of AMPK signaling is a common finding in different cancers, particularly LC. AMPK activation can significantly enhance LC metastasis via EMT induction. Upstream mediators such as PLAG1, IMPAD1, and TUFM can regulate AMPK-mediated metastasis. AMPK activation can promote proliferation and survival of LC cells via glycolysis induction. In suppressing LC progression, anti-tumor compounds including metformin, ginsenosides, casticin and duloxetine dually induce/inhibit AMPK signaling. This is due to double-edged sword role of AMPK signaling in LC cells. Furthermore, AMPK signaling can regulate response of LC cells to chemotherapy and radiotherapy that are discussed in the current review.

Keywords: AMPK; Apoptosis; Autophagy; Drug resistance; Lung cancer; Tumor microenvironment

DOI: https://doi.org/10.1016/j.lfs.2021.119649