Let‑7d inhibits colorectal cancer cell proliferation through the CST1/p65 pathway

Jiang,Jie; Liu,Hui-Ling; Tao,Li; Lin,Xian-Yi; Yang,Yi-Dong; Tan,Si-Wei; Wu,Bin

doi:10.3892/ijo.2018.4419

Let‑7d inhibits colorectal cancer cell proliferation through the CST1/p65 pathway

Authors:
- Jie Jiang
- Hui-Ling Liu
- Li Tao
- Xian-Yi Lin
- Yi-Dong Yang
- Si-Wei Tan
- Bin Wu
View Affiliations

Affiliations: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
Published online on: May 23, 2018 https://doi.org/10.3892/ijo.2018.4419
Pages: 781-790

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cystatin SN (cystatin 1, CST1) is a member of the cystatin superfamily which inhibits the proteolytic activity of cysteine proteases. CST1 is a tumor biomarker that provides useful information for the diagnosis of esophageal, gastric and colorectal carcinomas. MicroRNAs (miRNAs or miRs) play an important role in tumor cell proliferation. However, the exact role of let‑7d and CST1 in colon cancer remains unknown. The aim of this study was to assess whether let‑7d inhibits colorectal carcinogenesis through the CST1/p65 pathway, and determine whether it may be used as a potential target for clinical therapy. Microarray analysis of mRNAs extracted from colon cancer and normal tissues was performed. The results of gene expression microanalysis revealed that CST1 expression was upregulated in colon cancer compared with normal tissues. In addition, the upregulation of CST1 expression and the downregulation of let‑7d expression in patients with colon cancer and in several colorectal cancer cell lines were confirmed by reverse transcription-quantitative PCR (RT‑qPCR), immunohistochemistry and western blot analysis. In addition, siRNA targeting CST1 (CST1‑siRNA) and let‑7d-mimics were used in the HCT116 cells, and the results revealed that CST1 and let‑7d played a role in colorectal cancer cell proliferation. Let‑7d inhibited colorectal carcinogenesis through the CST1/p65 pathway. Thus, the findings of the present study indicate that CST1 may be a potential target for the future clinical therapy of colorectal cancer.

View Figures

View References

1	Vogelstein B and Kinzler KW: Cancer genes and the pathways they control. Nat Med. 10:789–799. 2004. View Article : Google Scholar : PubMed/NCBI
2	Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, Canli O, Heijmans J, Huels DJ, Moreaux G, et al: Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell. 152:25–38. 2013. View Article : Google Scholar : PubMed/NCBI
3	Li G, Ji XD, Gao H, Zhao JS, Xu JF, Sun ZJ, Deng YZ, Shi S, Feng YX, Zhu YQ, et al: EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex. Nat Commun. 3:6672012. View Article : Google Scholar : PubMed/NCBI
4	Hessmann E, Zhang JS, Chen NM, Hasselluhn M, Liou GY, Storz P, Ellenrieder V, Billadeau DD and Koenig A: NFATc4 regulates Sox9 gene expression in acinar cell plasticity and pancreatic cancer initiation. Stem Cells Int. 2016:52724982016. View Article : Google Scholar
5	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI
6	Jiang J, Liu HL, Liu ZH, Tan SW and Wu B: Identification of cystatin SN as a novel biomarker for pancreatic cancer. Tumour Biol. 36:3903–3910. 2015. View Article : Google Scholar : PubMed/NCBI
7	Choi EH, Kim JT, Kim JH, Kim SY, Song EY, Kim JW, Kim SY, Yeom YI, Kim IH and Lee HG: Upregulation of the cysteine protease inhibitor, cystatin SN, contributes to cell proliferation and cathepsin inhibition in gastric cancer. Clin Chim Acta. 406:45–51. 2009. View Article : Google Scholar : PubMed/NCBI
8	Chen YF, Ma G, Cao X, Luo RZ, He LR, He JH, Huang ZL, Zeng MS and Wen ZS: Overexpression of cystatin SN positively affects survival of patients with surgically resected esophageal squamous cell carcinoma. BMC Surg. 13:152013. View Article : Google Scholar : PubMed/NCBI
9	Yoneda K, Iida H, Endo H, Hosono K, Akiyama T, Takahashi H, Inamori M, Abe Y, Yoneda M, Fujita K, et al: Identification of Cystatin SN as a novel tumor marker for colorectal cancer. Int J Oncol. 35:33–40. 2009.PubMed/NCBI
10	Kumar MS, Pester RE, Chen CY, Lane K, Chin C, Lu J, Kirsch DG, Golub TR and Jacks T: Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev. 23:2700–2704. 2009. View Article : Google Scholar : PubMed/NCBI
11	Lambertz I, Nittner D, Mestdagh P, Denecker G, Vandesompele J, Dyer MA and Marine JC: Monoallelic but not biallelic loss of Dicer1 promotes tumorigenesis in vivo. Cell Death Differ. 17:633–641. 2010. View Article : Google Scholar
12	Büssing I, Slack FJ and Grosshans H: let-7 microRNAs in development, stem cells and cancer. Trends Mol Med. 14:400–409. 2008. View Article : Google Scholar : PubMed/NCBI
13	Lee YS and Dutta A: The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev. 21:1025–1030. 2007. View Article : Google Scholar : PubMed/NCBI
14	Boyerinas B, Park SM, Shomron N, Hedegaard MM, Vinther J, Andersen JS, Feig C, Xu J, Burge CB and Peter ME: Identification of let-7-regulated oncofetal genes. Cancer Res. 68:2587–2591. 2008. View Article : Google Scholar : PubMed/NCBI
15	Gurtan AM, Ravi A, Rahl PB, Bosson AD, JnBaptiste CK, Bhutkar A, Whittaker CA, Young RA and Sharp PA: Let-7 represses Nr6a1 and a mid-gestation developmental program in adult fibroblasts. Genes Dev. 27:941–954. 2013. View Article : Google Scholar : PubMed/NCBI
16	Jiao LR, Frampton AE, Jacob J, Pellegrino L, Krell J, Giamas G, Tsim N, Vlavianos P, Cohen P, Ahmad R, et al: MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors. PLoS One. 7:e320682012. View Article : Google Scholar : PubMed/NCBI
17	Volinia S, Galasso M, Sana ME, Wise TF, Palatini J, Huebner K and Croce CM: Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA. Proc Natl Acad Sci USA. 109:3024–3029. 2012. View Article : Google Scholar : PubMed/NCBI
18	Chang CJ, Hsu CC, Chang CH, Tsai LL, Chang YC, Lu SW, Yu CH, Huang HS, Wang JJ, Tsai CH, et al: Let-7d functions as novel regulator of epithelial-mesenchymal transition and chemoresistant property in oral cancer. Oncol Rep. 26:1003–1010. 2011.PubMed/NCBI
19	Ramberg H, Alshbib A, Berge V, Svindland A and Taskén KA: Regulation of PBX3 expression by androgen and Let-7d in prostate cancer. Mol Cancer. 10:502011. View Article : Google Scholar : PubMed/NCBI
20	Childs G, Fazzari M, Kung G, Kawachi N, Brandwein-Gensler M, McLemore M, Chen Q, Burk RD, Smith RV, Prystowsky MB, et al: Low-level expression of microRNAs let-7d and miR-205 are prognostic markers of head and neck squamous cell carcinoma. Am J Pathol. 174:736–745. 2009. View Article : Google Scholar : PubMed/NCBI
21	Tezcan G, Tunca B, Bekar A, Yalcin M, Sahin S, Budak F, Cecener G, Egeli U, Demir C, Guvenc G, et al: Ficus carica latex prevents invasion through induction of let-7d expression in GBM cell lines. Cell Mol Neurobiol. 35:175–187. 2015. View Article : Google Scholar
22	Nuovo GJ, Garofalo M, Valeri N, Roulstone V, Volinia S, Cohn DE, Phelps M, Harrington KJ, Vile R, Melcher A, et al: Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples. Mod Pathol. 25:1333–1344. 2012. View Article : Google Scholar : PubMed/NCBI
23	Ivo D'Urso P, Fernando D'Urso O, Damiano Gianfreda C, Mezzolla V, Storelli C and Marsigliante S: miR-15b and miR-21 as circulating biomarkers for diagnosis of glioma. Curr Genomics. 16:304–311. 2015. View Article : Google Scholar
24	Yu Y, Nangia-Makker P, Farhana L, G Rajendra S, Levi E and Majumdar AP: miR-21 and miR-145 cooperation in regulation of colon cancer stem cells. Mol Cancer. 14:982015. View Article : Google Scholar : PubMed/NCBI
25	Huang W, Lin J and Zhang H: miR-126: A novel regulator in colon cancer. Biomed Rep. 4:131–134. 2016. View Article : Google Scholar : PubMed/NCBI
26	Madison BB, Jeganathan AN, Mizuno R, Winslow MM, Castells A, Cuatrecasas M and Rustgi AK: Let-7 represses carcinogenesis and a stem cell phenotype in the intestine via regulation of Hmga2. PLoS Genet. 11:e10054082015. View Article : Google Scholar : PubMed/NCBI
27	Karin M and Greten FR: NNF-kappaB: Linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 5:749–759. 2005. View Article : Google Scholar : PubMed/NCBI
28	Lah TT, Babnik J, Schiffmann E, Turk V and Skaleric U: Cysteine proteinases and inhibitors in inflammation: Their role in periodontal disease. J Periodontol. 64(Suppl): 485–491. 1993.PubMed/NCBI
29	Travis J and Potempa J: Bacterial proteinases as targets for the development of second-generation antibiotics. Biochim Biophys Acta. 1477:35–50. 2000. View Article : Google Scholar : PubMed/NCBI
30	Koblinski JE, Ahram M and Sloane BF: Unraveling the role of proteases in cancer. Clin Chim Acta. 291:113–135. 2000. View Article : Google Scholar : PubMed/NCBI
31	Barrett AJ: The cystatins: A diverse superfamily of cysteine peptidase inhibitors. Biomed Biochim Acta. 45:1363–1374. 1986.PubMed/NCBI
32	Lindahl P, Abrahamson M and Björk I: Interaction of recombinant human cystatin C with the cysteine proteinases papain and actinidin. Biochem J. 281:49–55. 1992. View Article : Google Scholar : PubMed/NCBI
33	Dickinson DP, Thiesse M, Dempsey LD and Millar SJ: Genomic cloning, physical mapping, and expression of human type 2 cystatin genes. Crit Rev Oral Biol Med. 4:573–580. 1993. View Article : Google Scholar : PubMed/NCBI
34	Kim JT, Lee SJ, Kang MA, Park JE, Kim BY, Yoon DY, Yang Y, Lee CH, Yeom YI, Choe YK, et al: Cystatin SN neutralizes the inhibitory effect of cystatin C on cathepsin B activity. Cell Death Dis. 4:e9742013. View Article : Google Scholar : PubMed/NCBI