Hippo pathway: Regulation, deregulation and potential therapeutic targets in cancer

Mohajan, Suman; Jaiswal, Praveen Kumar; Vatanmakarian, Mousa; Yousefi, Hassan; Saikolappan, Sankaralingam; Alahari, Suresh K.; Koul, Sweaty; Koul, Hari K.

doi:10.1016/j.canlet.2021.03.006

Cited by 69 publications

(43 citation statements)

References 179 publications

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“…Dependent on the PBM, CLDN2 binds to and regulates the nuclear expression and activation of YAP [ 41 ]. The nuclear expression and activity of TAZ are also regulated by the upstream kinases of the Hippo pathway and other kinases such as c–SRC [ 42 , 43 ]. In gastric cancer cells, CLDN6 was reported to interact with LATS1/2 and reduce the level of p–YAP, thereby increasing the nuclear YAP activity [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

Wang

et al. 2021

IJMS

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Claudin 6 (CLDN6) was found to be a breast cancer suppressor gene, which is lowly expressed in breast cancer and inhibits breast cancer cell proliferation upon overexpression. However, the mechanism by which CLDN6 inhibits breast cancer proliferation is unclear. Here, we investigated this issue and elucidated the molecular mechanisms by which CLDN6 inhibits breast cancer proliferation. First, we verified that CLDN6 was lowly expressed in breast cancer tissues and that patients with lower CLDN6 expression had a worse prognosis. Next, we confirmed that CLDN6 inhibited breast cancer proliferation through in vitro and in vivo experiments. As for the mechanism, we found that CLDN6 inhibited c–MYC–mediated aerobic glycolysis based on a metabolomic analysis of CLDN6 affecting cellular lactate levels. CLDN6 interacted with a transcriptional co–activator with PDZ-binding motif (TAZ) and reduced the level of TAZ, thereby suppressing c–MYC transcription, which led to a reduction in glucose uptake and lactate production. Considered together, our results suggested that CLDN6 suppressed c–MYC–mediated aerobic glycolysis to inhibit the proliferation of breast cancer by TAZ, which indicated that CLDN6 acted as a novel regulator of aerobic glycolysis and provided a theoretical basis for CLDN6 as a biomarker of progression in breast cancer.

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Section: Discussionmentioning

confidence: 99%

CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

Wang

et al. 2021

IJMS

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“…YAP, playing an essential role in cancer progression, was reported to be implicated in modulating various malignant phenotypes of cancer cells, such as cell proliferation, migration, invasion, apoptosis resistance, EMT phenotype, and stemness properties [44][45][46]. In this study, data from the TCGA database exhibited a close association between CHRNA5 and the Hippo signaling pathway in HCC.…”

Section: Discussionmentioning

confidence: 56%

CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity

et al. 2022

Pharmaceutics

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Hepatocellular carcinoma (HCC) is a major health concern worldwide. A better understanding of the mechanisms underlying the malignant phenotype is necessary for developing novel therapeutic strategies for HCC. Signaling pathways initiated by neurotransmitter receptors, such as α5-nicotinic acetylcholine receptor (CHRNA5), have been reported to be implicated in tumor progression. However, the functional mechanism of CHRNA5 in HCC remains unclear. In this study, we explored the role of CHRNA5 in HCC and found that CHRNA5 expression was increased in human HCC tissues and positively correlated with the T stage (p < 0.05) and AJCC phase (p < 0.05). The KM plotter database showed that the high expression level of CHRNA5 was strongly associated with worse survival in HCC patients. Both in vitro and in vivo assays showed that CHRNA5 regulates the proliferation ability of HCC by regulating YAP activity. In addition, CHRNA5 promotes the stemness of HCC by regulating stemness-associated genes, such as Nanog, Sox2 and OCT4. Cell migration and invasion assays demonstrated that CHRNA5 significantly enhanced the metastasis of HCC by regulating epithelial–mesenchymal transition (EMT)-associated genes. Furthermore, we found that CHRNA5 regulates the sensitivity of sorafenib in HCC. Our findings suggest that CHRNA5 plays a key role in the progression and drug resistance of HCC, and targeting CHRNA5 may be a strategy for the treatment of HCC.

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“…In additional, they demonstrated that miR-135b, miR-135a targeted angiomotin-like2 (AMOTL2), and the expression of AMOTL2 can be increased through miR-135b and miR-135a inhibition. This result might be a clue that exosomal miR-135b and miR-135a derived from BTSCs may be able to regulate the Hippo pathway via AMOTL2, which plays a significant role in chemoresistance (Mohajan et al, 2021;Zeng and Dong, 2021).…”

Section: High-grade Meningiomas and Medulloblastomamentioning

confidence: 86%

The Role of MicroRNAs in Therapeutic Resistance of Malignant Primary Brain Tumors

Gareev

Beylerli

Liang

et al. 2021

Front. Cell Dev. Biol.

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Brain tumors in children and adults are challenging tumors to treat. Malignant primary brain tumors (MPBTs) such as glioblastoma have very poor outcomes, emphasizing the need to better understand their pathogenesis. Developing novel strategies to slow down or even stop the growth of brain tumors remains one of the major clinical challenges. Modern treatment strategies for MPBTs are based on open surgery, chemotherapy, and radiation therapy. However, none of these treatments, alone or in combination, are considered effective in controlling tumor progression. MicroRNAs (miRNAs) are 18–22 nucleotide long endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level by interacting with 3′-untranslated regions (3′-UTR) of mRNA-targets. It has been proven that miRNAs play a significant role in various biological processes, including the cell cycle, apoptosis, proliferation, differentiation, etc. Over the last decade, there has been an emergence of a large number of studies devoted to the role of miRNAs in the oncogenesis of brain tumors and the development of resistance to radio- and chemotherapy. Wherein, among the variety of molecules secreted by tumor cells into the external environment, extracellular vesicles (EVs) (exosomes and microvesicles) play a special role. Various elements were found in the EVs, including miRNAs, which can be transported as part of these EVs both between neighboring cells and between remotely located cells of different tissues using biological fluids. Some of these miRNAs in EVs can contribute to the development of resistance to radio- and chemotherapy in MPBTs, including multidrug resistance (MDR). This comprehensive review examines the role of miRNAs in the resistance of MPBTs (e.g., high-grade meningiomas, medulloblastoma (MB), pituitary adenomas (PAs) with aggressive behavior, and glioblastoma) to chemoradiotherapy and pharmacological treatment. It is believed that miRNAs are future therapeutic targets in MPBTs and such the role of miRNAs needs to be critically evaluated to focus on solving the problems of resistance to therapy this kind of human tumors.

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Hippo pathway: Regulation, deregulation and potential therapeutic targets in cancer

Cited by 69 publications

References 179 publications

CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity

The Role of MicroRNAs in Therapeutic Resistance of Malignant Primary Brain Tumors

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