The CD44high Tumorigenic Subsets in Lung Cancer Biospecimens Are Enriched for Low miR-34a Expression

Basak, Sayan; Veena, Mysore S.; Oh, Scott; Lai, Chi; Vangala, Sitaram; Elashoff, David; Fishbein, Michael C.; Sharma, Sanjai; Rao, Nagesh; Rao, Dinesh S.; Phan, Ryan T.; Srivatsan, Eri S.; Batra, Raj K.

doi:10.1371/journal.pone.0073195

Cited by 22 publications

(29 citation statements)

References 39 publications

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“…Immunofluorescence was performed using anti-cystatin E/M antibody (R & D Systems, Minneapolis, MN) by following the established protocol (19). (41). Normal cervix tissue was used as a control.…”

Section: Methodsmentioning

confidence: 99%

Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB

Soh

Venkatesan

Veena

et al. 2016

Molecular and Cellular Biology

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Cervical cancer is the second-most-common cancer responsible for cancer-related death in women around the world. The incidence is increasing, with 450,000 new cases diagnosed worldwide and 12,340 diagnosed in the United States annually (1, 2). It is the third leading cause of death from cancer in women 15 to 34 years of age and the fifth leading cause of death in women 35 to 54 years of age, representing about 2% of all cancers in women in the United States. The disease is frequently found in women who have had multiple sex partners, smoking habits, and immune system dysfunctions (3). Cervical cancer is closely linked with human papillomavirus (HPV) infection, and HPVs are detected in 90% of cervical cancer lesions (4-6). While the E6 protein of HPV inactivates p53 and E7 inactivates the retinoblastoma (Rb) tumor suppressor protein, detailed studies on a large number of tumors indicate that viral infection alone is not sufficient for tumor development. Studies have also shown that 20 to 30 million Americans are infected with HPV (7). However, only those in a subset develop cervical cancer. Recently, HPVs have been implicated in the development of head and neck, lung, and breast cancers (8-10).Cystatins are inhibitors of cysteine proteases and are classified into a large superfamily subdivided into three families based on their location, size, and complexity of polypeptide chains (11-13). Cystatin E/M belongs to the type 2 cystatin family (cystatin C, D, E/M, F, S, SA, and SN), whose members are mainly secreted, and most of them are found abundantly in body fluids and tissues. Cystatin E/M is present as an unglycosylated 14-kDa form containing 149 amino acids and a 17-kDa form that is glycosylated. Loss of this protein seems to play a significant role in abnormal skin development (14). A null mutation of the mouse cystatin E/M gene is also correlated with development of the ichq phenotype, characterized by neonatal lethality, abnormal cornification, and desquamation. Cystatin E/M was initially identified as a downregulated transcript in metastatic breast cancers (15,16). A number of studies have implicated cystatin E/M as a human tumor suppressor gene that is inactivated in the cancers of the breast, cervix, prostate, brain, and stomach (17-23). Our studies have also shown that the inactivation of the gene is associated with homozygous deletion, promoter hypermethylation, and somatic mutations in primary tumor samples (19). Cystatin E/M gene is expressed in ductal carcinoma in situ (DCIS) but not in metastatic breast cancer, pointing to inactivation during tumor progression (16)(17)(18)24). Finally, inactivation of cystatin E/M gene is associated with the loss of expression of estrogen and progesterone receptors and HER4, indicating an association with these proteins in the development of invasive breast cancers (25). However, the molecular mechanism of cystatin E/M-mediated tumor cell growth inhibition is not yet understood.Cathepsins include a broad range of proteases, the serine (A

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Section: Methodsmentioning

confidence: 99%

Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB

Soh

Venkatesan

Veena

et al. 2016

Molecular and Cellular Biology

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“…Immunohistochemistry-Paraffin sections (5 m) of tumor samples were dewaxed and hybridized to p16 antibody after standard immunohistochemical protocol (19). Two pathologists were involved in independent scoring of hybridization intensities.…”

Section: Methodsmentioning

confidence: 99%

p16 Protein and Gigaxonin Are Associated with the Ubiquitination of NFκB in Cisplatin-induced Senescence of Cancer Cells

Veena

Wilken

Zheng

et al. 2014

Journal of Biological Chemistry

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Background: Molecular mechanism of p16-mediated cellular senescence in cisplatin-treated cells is not known. Results: Cisplatin treatment leads to p16 nuclear transport and association with gigaxonin for the ubiquitination of NFB. Conclusion: A protein associated with neural diseases is involved in cisplatin-mediated cellular senescence. Significance: Nuclear expression of p16 and gigaxonin is a useful marker of cancer cell chemosensitivity.

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“…It has been reported that the CD44 (high) tumorigenic subsets in lung cancer biospecimens are enriched for low miR-34a expression [49]. In xenograft tumor model, miR-34a has been shown to negatively regulate the tumorigenic properties of high CD44 expression lung CSCs [22].…”

Section: Discussionmentioning

confidence: 99%

Activation of p53/miR‐34a Tumor Suppressor Axis by Chinese Herbal Formula JP‐1 in A549 Lung Adenocarcinoma Cells

Yao

Chow

Lin

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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Lung cancer is the leading cause of cancer death worldwide; the most common pathologic type is lung adenocarcinoma (LADC). In spite of the recent progress in targeted therapy, most LADC patients eventually expired due to the inevitable recurrence and drug resistance. New complementary agent with evidence-based molecular mechanism is urgently needed. MiR-34a is an important p53 downstream tumor suppressor, which regulates apoptosis, cell-cycle, EMT (epithelial mesenchymal transition), and so forth. Its expression is deficient in many types of cancers including LADC. Here, we show that a Chinese herbal formula JP-1 activates p53/miR-34a axis in A549 human LADC cells (p53 wild-type). Treatment with JP-1 induces p53 and its downstream p21 and BAX proteins as well as the miR-34a, resulting in growth inhibition, colony formation reduction, migration repression, and apoptosis induction. Accordingly, the decreases of miR-34a downstream targets such as CDK6, SIRT1, c-Myc, survivin, Snail, and AXL were observed. Moreover, JP-1 activates AMPKα and reduces mTOR activity, implying its inhibitory effect on the energy-sensitive protein synthesis and cell proliferation signaling. Our results show that JP-1 activates p53/miR-34a tumor suppressor axis and decreases proteins related to proliferation, apoptosis resistance, and metastasis, suggesting its potential as a complementary medicine for LADC treatment.

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The CD44high Tumorigenic Subsets in Lung Cancer Biospecimens Are Enriched for Low miR-34a Expression

Cited by 22 publications

References 39 publications

Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB

Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB

p16 Protein and Gigaxonin Are Associated with the Ubiquitination of NFκB in Cisplatin-induced Senescence of Cancer Cells

Activation of p53/miR‐34a Tumor Suppressor Axis by Chinese Herbal Formula JP‐1 in A549 Lung Adenocarcinoma Cells

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