mir-660-p53-mir-486 Network: A New Key Regulatory Pathway in Lung Tumorigenesis

Borzi, Cristina; Calzolari, Linda; Centonze, Giovanni; Milione, Massimo; Sozzi, Gabriella; Fortunato, Orazio

doi:10.3390/ijms18010222

Cited by 31 publications

(31 citation statements)

References 40 publications

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“…17,18 In this regard, several miRNAs have been reported to suppress or promote lung cancer cell survival or death. [19][20][21][22] Consistent with these reports, we have previously reported that miR-886-3Pwas associated with survival of SCL. 23 In the current study, we further investigated role of miR-886-3P in regulating small cell lung caner cell proliferation, migration, colony formation, mesenchymal-epithelial transition (MET), and in vivo xenograft tumor formation and growth.…”

Section: Introductionsupporting

confidence: 86%

MicroRNA-886-3P functions as a tumor suppressor in small cell lung cancer

Shen

Zhou

et al. 2018

Cancer Biology & Therapy

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Small cell lung cancer (SCLC) is a highly aggressive disease and miRNAs may play an important role in modulating SCLC progression. We have previously screened 924 miRNAs and found that miR-886-3P was negatively associated with SCLC survival. In the current study, we further investigated the role of miR-886-3P mimic in regulating SCLC cell phenotypic alteration in vitro and xenograft tumor formation in vivo. We found that transfection of miR-886-3P mimic significantly inhibited SCLC cell proliferation, migration, and colony formation, and induced mesenchymal-epithelial transition (MET) by suppressing TGF-ß1 synthesis in vitro. Furthermore, intra-tumor injection of miR-886-3P mimic lead to necrosis and suppression of tumor invasion to the surrounding tissue in the subcutaneous xenograft tumor, and intra-vein injection of miR-886-3P mimic suppressed xenograft lung cancer growth in vivo. These findings suggested that miR-886-3P functions as a tumor suppressor in SCLC and thus, it might be a potential therapeutic molecule in the treatment of lung cancer.

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Section: Introductionsupporting

confidence: 86%

MicroRNA-886-3P functions as a tumor suppressor in small cell lung cancer

Shen

Zhou

et al. 2018

Cancer Biology & Therapy

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“…Several lines of evidence have indicated that miRNAs play a crucial role in tumor formation and progression . Previous studies have revealed that miR‐660‐5p is dysregulated in several human malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…They modulate the expression of target genes by interacting with the 3' untranslated regions (3'‐UTRs) of target mRNA and play an essential role in the biological and pathological processes of various diseases . Many studies have also indicated that microRNAs can modulate tumor initiation and progression and function in tumor cell invasion and metastasis . Studies have shown that miR‐660‐5p regulates the malignancy of breast cancer cells by suppressing the expression of TFCP2, and is a novel therapeutic target for clinical treatment and a potential prognostic indicator .…”

Section: Introductionmentioning

confidence: 99%

“…11,12 Many studies have also indicated that microRNAs can modulate tumor initiation and progression and function in tumor cell invasion and metastasis. [13][14][15][16] Studies have shown that miR-660-5p regulates the malignancy of breast cancer cells by suppressing the expression of TFCP2, and is a novel therapeutic target for clinical treatment and a potential prognostic indicator. 17,18 Moreover, miR-660-5p acts as a tumor suppressor in renal cell carcinoma and may regulate cell migration, proliferation, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…Several lines of evidence have indicated that miRNAs play a crucial role in tumor formation and progression. [13][14][15][16] Previous studies have revealed that miR-660-5p is dysregulated in several human malignancies. For example, miR-660-5p is upregulated in breast cancer, and it may be a potential oncogene that plays a vital role in the development and metastasis of breast cancer.…”

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Nm23‐H1 inhibits lung cancer bone‐specific metastasis by upregulating miR‐660‐5p targeted SMARCA5

Deng

et al. 2020

Thoracic Cancer

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Background Nm23‐H1 gene has been found to be an inhibitor of tumor metastasis in lung cancer. MicroRNAs (miRNAs) play key roles in tumor metastasis through multiple signaling pathways. This study explored whether the nm23‐H1 gene could inhibit invasion and metastasis of lung cancer cells by regulating miRNA‐660‐5p targets. Methods Quantitative real‐time PCR (qRT‐PCR) and western blots were used to measure the expression of nm23‐H1 and miR‐660‐5p of various human lung cancer cell lines. Cell counting kit‐8 (CCK‐8), wound‐healing and transwell assay were carried out to assess cell proliferation, migration and invasion of each cell line. Xenograft were applied to determine in vivo effects of miR‐660‐5p among nude mice. Luciferase assay and western blot were performed to determine the target gene of miR‐660‐5p. Results We found that high expression of nm23‐H1 correlated with decreased miRNA‐660‐5p expression. Inhibiting miR‐660‐5p suppressed lung cancer cells progression significantly in vitro, whereas overexpression of miR‐660‐5p facilitated tumor growth and bone metastasis in vivo. In addition, as the potential target gene of miR‐660‐5p, SMARCA5 overexpression in vitro suppressed tumor progression and osteolytic metastasis associated RANKL signaling, which is congruent with the effect of nm23‐H1 on the lung cancer cells. Conclusion Nm23‐H1 inhibits tumor progression and bone‐specific metastasis of lung cancer by regulating miR‐660‐5p/SMARCA5/RANKL axis, which indicates the related genes may serve as potential targets for the treatment of human lung cancer. Key points Significant findings of the study High expression of nm23‐H1 correlated with decreased miRNA‐660‐5p expression. Further, downregulation of miR‐660‐5p significantly suppressed the tumor progression and bone‐specific metastasis of lung cancer cells. What this study adds This is the first study to show an inverse association between nm23‐H1 and miR‐660‐5p, and confirm that nm23‐H1 inhibits tumor progression and bone‐specific metastasis of lung cancer by regulating miR‐660‐5p/SMARCA5/RANKL axis.

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Aging‐associated skeletal muscle defects in HER2/Neu transgenic mammary tumour model

Wang

Kumar

Bhat‐Nakshatri

et al. 2020

JCSM Rapid Communications

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Background Loss of skeletal muscle volume and functional limitations are poor prognostic markers in breast cancer patients. Several molecular defects in skeletal muscle including reduced myoblast determination protein 1 (MyoD) levels and increased protein turn over due to enhanced proteosomal activity have been suggested as causes of skeletal muscle loss in cancer patients. However, it is unknown whether molecular defects in skeletal muscle are dependent on tumour aetiology. Methods We characterized functional and molecular defects of skeletal muscle in mouse mammary tumour virus (MMTV)-Neu (Neu+) mice (n = 6-12), an animal model that represents HER2 + human breast cancer, and compared the results with well-characterized luminal B breast cancer model MMTV-PyMT (PyMT+). Functional studies such as grip strength, rotarod performance, and ex vivo muscle contraction were performed to measure the effects of cancer on skeletal muscle. Expression of muscle-enriched genes and microRNAs as well as circulating cytokines/chemokines were measured. Because nuclear factor-kappaB (NF-κB) pathway plays a significant role in skeletal muscle defects, the ability of NF-κB inhibitor dimethylaminoparthenolide (DMAPT) to reverse skeletal muscle defects was examined. Results Neu+ mice showed skeletal muscle defects similar to accelerated aging. Compared with age and sex-matched wild type mice, Neu+ tumour-bearing mice had lower grip strength (202 ± 6.9 vs. 179 ± 6.8 g grip force, P = 0.0069) and impaired rotarod performance (108 ± 12.1 vs. 30 ± 3.9 s, P < 0.0001), which was consistent with reduced muscle contractibility (P < 0.0001). Skeletal muscle of Neu+ mice (n = 6) contained lower levels of CD82 + (16.2 ± 2.9 vs. 9.0 ± 1.6) and CD54 + (3.8 ± 0.5 vs. 2.4 ± 0.4) muscle stem and progenitor cells (P < 0.05), suggesting impaired capacity of muscle regeneration, which was accompanied by decreased MyoD, p53, and miR-486 expression in muscles (P < 0.05). Unlike PyMT+ mice, which showed skeletal muscle mitochondrial defects including reduced mitochondria levels and peroxisome proliferator-activated receptor gamma co-activator 1 (beta), Neu + mice displayed accelerated aging-associated changes including muscle fibre shrinkage and increased extracellular matrix deposition. Circulating 'aging factor' and cachexia and fibromyalgia-associated chemokine CC motif chemokine ligand 11 (Ccl11) was elevated in Neu+ mice (1439.56 ± 514 vs. 1950 ± 345 pg/mL, P < 0.05). Treatment of Neu+ mice with DMAPT significantly restored grip strength (205 ± 6 g force), rotarod performance (74 ± 8.5 s), reversed molecular alterations associated with skeletal muscle aging, reduced circulating Ccl11 (1083.26 ± 478 pg/mL), and improved animal survival. Conclusions These results suggest that breast cancer subtype has a specific impact on the type of molecular and structural changes in skeletal muscle, which needs to be taken into consideration while designing therapies to reduce breast cancer-induced skeletal muscle loss and functional limitations.

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mir-660-p53-mir-486 Network: A New Key Regulatory Pathway in Lung Tumorigenesis

Cited by 31 publications

References 40 publications

MicroRNA-886-3P functions as a tumor suppressor in small cell lung cancer

MicroRNA-886-3P functions as a tumor suppressor in small cell lung cancer

Nm23‐H1 inhibits lung cancer bone‐specific metastasis by upregulating miR‐660‐5p targeted SMARCA5

Aging‐associated skeletal muscle defects in HER2/Neu transgenic mammary tumour model

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