microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKβ-mTORC1 axis to regulate renal cancer cell invasion

Bera, Amit; Das, Falguni; Ghosh‐Choudhury, Nandini; Kasinath, Balakuntalam S.; Abboud, Hanna E.; Choudhury, Goutam Ghosh

doi:10.1016/j.yexcr.2014.06.022

Cited by 45 publications

(48 citation statements)

References 127 publications

(170 reference statements)

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“…We also found that miR-21 remarkably increased invasion and migration in SACC cells, these results are consistent with previous findings from other cancers. 21,22,43,44 In addition, we showed that knockdown of miR-21 could dramatically decrease cell invasion and migration in SACC cells. Overexpression of miR-21 has been reported in various human cancers.…”

Section: Discussionmentioning

confidence: 82%

“…22,47,48 It performs an important function in tumor invasion and metastasis through inhibition of STAT3 activation, which are known to be involved in cancer progression. 22,[47][48][49] Our data suggested that PDCD4 expression has a negative correlation with the expression of miR-21 in SACC tissues and cell lines at protein level. Applying specific inhibitor of miR-21 can rescue PDCD4 expression, negatively regulated SACC cell invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…21 Recently, Bera et al identify a previously unrecognized signaling node where high miR-21 levels reduce rictor-programmed cell death 4 (PDCD4) interaction to increase phosphorylation of Akt and contribute to metastatic fitness of renal cancer cells. 22 The relationship between miRNAs and signaling pathways in SACC is extremely complicated.…”

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confidence: 99%

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miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma

Jiang

Hou

et al. 2015

Laboratory Investigation

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miR-21, which is a putative tumor onco-miR and frequently overexpressed microRNA in various tumors, has been linked to tumor progression through targeting of tumor-suppressor genes. In this study, we sought to determine whether miR-21 has any role on tumor progression of salivary adenoid cystic carcinoma (SACC) and the possible mechanisms. We found that the level of miR-21 expression was significantly higher in SACC than that in normal salivary tissues, and it is also higher in tumors with metastasis than that without metastasis. Using an anti-miR-21 inhibitor in an in vitro model, downregulation of miR-21 significantly decreased the capacity of invasion and migration of SACC cells, whereas a pre-miR-21 increased the capacity of invasion and migration of SACC cells. To explore the potential mechanisms by which miR-21 regulate invasion and migration, we identified one direct miR-21 target gene, programmed cell death 4 (PDCD4), which has been implicated in invasion and metastasis Salivary adenoid cystic carcinoma (SACC) is one of the most common malignancy of the salivary gland, accounting for 10% of salivary gland tumors and 30% of human salivary gland malignancies. 1,2 SACC is characterized by slow but aggressive growth, nerve and blood vessel invasion, multiple recurrences, and distant metastases. 3-5 Lung metastasis and nerve metastasis are the biological characteristics of SACC. [6][7][8] It has been reported that the incidence of SACC with distant metastasis ranged from 35 to 50% of all cases. Lung was the most common organ of its distant metastasis, and lung metastasis is still the leading death cause of patients with SACC. 4,5 Although the 5-year survival rate is high for patients with SACC, probably because of the slow growth of the tumor, the 10-and 15-year prognoses are poor because of the frequent local recurrences and distant metastases. [6][7][8] Although multiple genetic and epigenetic alterations have been detected in SACC, 3,9-13 the precise molecular mechanisms of progression and metastasis of SACC remain unknown.MicroRNAs (miRNAs) are small non-coding RNA molecules, with a length of 20-22 nucleotides, that regulate gene expression by either translational inhibition or mRNA degradation. miRNAs function as either oncogenes or tumor suppressors by inhibiting the expression of target genes, some of which are either directly or indirectly involved with canonical signaling pathways. 13,14 The roles and function of some selected miRNAs in SACC have been reported. 15

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma

Jiang

Hou

et al. 2015

Laboratory Investigation

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“…The ACHN and 786-O renal carcinoma cells were obtained from American Type Culture Collection, Manassas, VA. These cells were grown in RPMI 1640 medium containing 10% fetal bovine serum in the presence of penicillin/streptomycin (28,29). The A498 and RCC4 renal carcinoma cells were kindly provided by Dr. Karen Block (University of Texas Health Science Center at San Antonio).…”

Section: Methodsmentioning

confidence: 99%

“…Equal amounts of proteins present in the cell extracts were separated by SDS-PAGE. The proteins were transferred to PVDF membrane and immunoblotted with the indicated antibodies as described previously (28,29).…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells

Das

Dey

Bera

et al. 2016

Journal of Biological Chemistry

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Renal cell carcinoma (RCC)5 accounts for nearly 3% of all malignancies. Among the five histologic subtypes, clear cell renal carcinoma accounts for about 85% of all RCCs (1, 2). About 30% of patients show renal cancer metastasis to lung, liver, bone, and brain at the time of diagnosis, and half of the remaining patients eventually develop metastasis (3-5). Individuals bearing germ line mutation in the von Hippel-Lindau (VHL) tumor suppressor gene located on chromosome 3p have increased risk for clear cell RCC. Inherited forms of RCC occur when the remaining wild type VHL allele is lost.Apart from inactivated VHL-driven tumorigenesis, IGF-1 signal transduction significantly contributes to the growth of RCC cells in vitro and in vivo in animal models (6, 7). In fact, increased IGF-1 mRNA and protein levels in the kidney are significantly higher in RCC in humans (8, 9). Similarly, IGF-1 receptor (IGF-1R) expression has also been shown to be significantly associated with increased risk of RCC (10, 11). Also, patients with IGF-1R-positive RCC showed significantly reduced survival rates (12, 13). The dimeric IGF-1R shares significantly high homology with insulin receptor. IGF-1R is produced as a single polypeptide, which is cleaved to form the mature ␣-and ␤-subunits. The ␣-protein represents the transmembrane protein with extracellular domain, whereas the ␤-subunit is exclusively intracellular. The IGF-1 binds to the extracellular domain of ␣-subunit, resulting in heterotetramerization. Upon ligand binding, conformational change in the juxtamembrane domain induces an increase in tyrosine kinase activity of the ␤-subunit, which autophosphorylates specific tyrosine residues in the ␤-subunit. Tyrosine-phosphorylated ␤-subunit recruits the IRS protein through binding to its N-terminal PTB domain. Receptor-bound IRS protein serves as docking sites for the Src homology 2 domain-containing proteins, which trigger signal transduction to induce tumor growth of RCC mainly by two arms, the Ras/MAPK and phosphatidylinositol 3-kinase/Akt pathways (14, 15). Because of significant homology between IGF-1R and insulin receptor, they can form a hybrid receptor, which binds IGF-1 with an affinity similar to that with IGF-1R heterotetramer alone, and can elicit mitogenic signal transduction in tumor cells (14,15). Therefore, * This work was supported in part by the Veterans Affairs Research Service Merit Review Grant 2 I01 BX000926 and National Institutes of Health Grant RO1 DK50190 (to G. G. C.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We dedicate this paper to Dr. Hanna E. Abboud, who unexpectedly left us on January 7, 2015. His continued encouragement and support were vital for the completion of this work. 1 Both authors contributed equally to this work. 2 Supported by Veterans Affairs Merit Review Grant 5I01BX001340. 3 Supported by V...

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PLEKHA5 regulates tumor growth in metastatic melanoma

Zhang

Zhu

Deng

et al. 2019

Cancer

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Background PLEKHA5 has previously been identified as a novel molecule implicated in melanoma brain metastasis, a disease that continues to portend a poor prognosis. The aim of this study was to further investigate the functional role of PLEKHA5 in disseminated melanoma. Methods The impact of PLEKHA5 on proliferation and tumor growth was examined in vitro and in melanoma xenograft models, including brain‐tropic melanomas (melanomas tending to disseminate to the brain). In vitro loss‐ and gain‐of‐function studies were used to explore the underlying mechanisms of PLEKHA5‐mediated tumor growth and the crosstalk between PLEKHA5 and PI3K/AKT/mTOR or MAPK/ERK signaling. The clinical relevance of PLEKHA5 dysregulation was further investigated in a cohort of matched cranial and extracranial melanoma metastases. Results PLEKHA5 stable knockdown negatively regulated cell proliferation by inhibiting the G1‐to‐S cell cycle transition, which coincided with upregulation of the cell cycle regulator PDCD4. Conversely, ectopic PLEKHA5 expression exhibited the inverse effect. PLEKHA5 knockdown significantly inhibited tumor growth, whereas its overexpression upregulated the growth of tumors, which was induced by cranial and subcutaneous inoculation of cells in nude mice. PLEKHA5 modulation affected PDCD4 protein stability and was coupled with changes in PI3K/AKT/mTOR pathway signaling. High PDCD4 expression in cerebral specimens was associated with better overall survival. Conclusions This study further supports the role of PLEKHA5 as a regulator of melanoma growth at distant sites, including the brain. Furthermore, the results highlight the significance of PDCD4 dysregulation in disseminated melanoma and implicate PDCD4 as a possible causal link between PLEKHA5 and cell proliferation and growth.

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microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKβ-mTORC1 axis to regulate renal cancer cell invasion

Cited by 45 publications

References 127 publications

miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma

miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma

MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells

PLEKHA5 regulates tumor growth in metastatic melanoma

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