MACC1 overexpression in carcinoma‑associated fibroblasts induces the invasion of lung adenocarcinoma cells via paracrine signaling

Li,Zhuoshi; Guo,Tao; Fang,Lei; Li,Nan; Wang,Xiaochao; Wang,Peng; Zhao,Shilei; Li,Fengzhou; Cui,Yanwei; Shu,Xin; Zhao,Lei; Li,Jinxiu; Gu,Chundong

doi:10.3892/ijo.2019.4702

MACC1 overexpression in carcinoma‑associated fibroblasts induces the invasion of lung adenocarcinoma cells via paracrine signaling

Authors:
- Zhuoshi Li
- Tao Guo
- Lei Fang
- Nan Li
- Xiaochao Wang
- Peng Wang
- Shilei Zhao
- Fengzhou Li
- Yanwei Cui
- Xin Shu
- Lei Zhao
- Jinxiu Li
- Chundong Gu
View Affiliations

Affiliations: Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, P.R. China, Lung Cancer Diagnosis and Treatment Center of Dalian, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
Published online on: January 30, 2019 https://doi.org/10.3892/ijo.2019.4702
Pages: 1367-1375

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

Carcinoma‑associated fibroblasts (CAFs) are essential for initiating lung cancer cell invasion and metastasis. An elevated MACC1 expression has been implicated in the progression of lung adenocarcinoma. Hitherto, the role of MACC1 in lung adenocarcinoma‑derived CAFs remains unclear. In this study, CAFs isolated from the tissues of patients with lung adenocarcinoma expressed typical CAF markers (shown by immunohistochemical and immunofluorescence analysis) and exhibited enhanced migration and invasion abilities when co‑cultured with A549 cells in a microfluidic model. MACC1‑overexpressing CAFs not only demonstrated an increased invasion, but also exerted a promoting effect on the invasion of tumor cells. The reduced expression of MACC1 impaired the invasive ability of the CAFs. Western blot analysis and RT‑qPCR analysis demonstrated that multiple paracrine pathways were activated in the MACC1‑overexpressing CAFs. Overall, this study presents a novel role of MACC1 in CAF‑induced lung adenocarcinoma cell invasion, which possibly occurs via paracrine signaling. Furthermore, MACC1 was indicated to be a potential therapeutic target for lung adenocarcinoma.

View Figures

View References

1	Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, Bannon F, Ahn JV, Johnson CJ, Bonaventure A, et al CONCORD Working Group: Global surveillance of cancer survival 1995-2009: Analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 385:977–1010. 2015. View Article : Google Scholar
2	Langer CJ, Besse B, Gualberto A, Brambilla E and Soria JC: The evolving role of histology in the management of advanced non-small-cell lung cancer. J Clin Oncol. 28:5311–5320. 2010. View Article : Google Scholar : PubMed/NCBI
3	Perlikos F, Harrington KJ and Syrigos KN: Key molecular mechanisms in lung cancer invasion and metastasis: A comprehensive review. Crit Rev Oncol Hematol. 87:1–11. 2013. View Article : Google Scholar : PubMed/NCBI
4	Kalluri R and Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer. 6:392–401. 2006. View Article : Google Scholar : PubMed/NCBI
5	Gupta GP and Massagué J: Cancer metastasis: Building a framework. Cell. 127:679–695. 2006. View Article : Google Scholar : PubMed/NCBI
6	Shekhar MP, Pauley R and Heppner G: Host microenvironment in breast cancer development: Extracellular matrix-stromal cell contribution to neoplastic phenotype of epithelial cells in the breast. Breast Cancer Res. 5:130–135. 2003. View Article : Google Scholar : PubMed/NCBI
7	Olaso E, Salado C, Egilegor E, Gutierrez V, Santisteban A, Sancho-Bru P, Friedman SL and Vidal-Vanaclocha F: Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis. Hepatology. 37:674–685. 2003. View Article : Google Scholar : PubMed/NCBI
8	Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL and Weinberg RA: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 121:335–348. 2005. View Article : Google Scholar : PubMed/NCBI
9	De Wever O and Mareel M: Role of tissue stroma in cancer cell invasion. J Pathol. 200:429–447. 2003. View Article : Google Scholar : PubMed/NCBI
10	Ostman A and Augsten M: Cancer-associated fibroblasts and tumor growth–bystanders turning into key players. Curr Opin Genet Dev. 19:67–73. 2009. View Article : Google Scholar : PubMed/NCBI
11	Xing F, Saidou J and Watabe K: Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci. 15:166–179. 2010. View Article : Google Scholar :
12	Unger C, Kramer N, Unterleuthner D, Scherzer M, Burian A, Rudisch A, Stadler M, Schlederer M, Lenhardt D, Riedl A, et al: Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms. Oncogene. 36:5341–5355. 2017. View Article : Google Scholar : PubMed/NCBI
13	Teng F, Tian WY, Wang YM, Zhang YF, Guo F, Zhao J, Gao C and Xue FX: Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis. J Hematol Oncol. 9:82016. View Article : Google Scholar : PubMed/NCBI
14	Kuzet SE and Gaggioli C: Fibroblast activation in cancer: When seed fertilizes soil. Cell Tissue Res. 365:607–619. 2016. View Article : Google Scholar : PubMed/NCBI
15	Neri S, Hashimoto H, Kii H, Watanabe H, Masutomi K, Kuwata T, Date H, Tsuboi M, Goto K, Ochiai A, et al: Cancer cell invasion driven by extracellular matrix remodeling is dependent on the properties of cancer-associated fibroblasts. J Cancer Res Clin Oncol. 142:437–446. 2016. View Article : Google Scholar
16	Stein U, Walther W, Arlt F, Schwabe H, Smith J, Fichtner I, Birchmeier W and Schlag PM: MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med. 15:59–67. 2009. View Article : Google Scholar
17	Arlt F and Stein U: Colon cancer metastasis: MACC1 and Met as metastatic pacemakers. Int J Biochem Cell Biol. 41:2356–2359. 2009. View Article : Google Scholar : PubMed/NCBI
18	Wang L, Wu Y, Lin L, Liu P, Huang H, Liao W, Zheng D, Zuo Q, Sun L, Huang N, et al: Metastasis-associated in colon cancer-1 upregulation predicts a poor prognosis of gastric cancer, and promotes tumor cell proliferation and invasion. Int J Cancer. 133:1419–1430. 2013. View Article : Google Scholar : PubMed/NCBI
19	Huang Y, Zhang H, Cai J, Fang L, Wu J, Ye C, Zhu X and Li M: Overexpression of MACC1 and Its significance in human Breast Cancer Progression. Cell Biosci. 3:162013. View Article : Google Scholar : PubMed/NCBI
20	Ji D, Lu ZT, Li YQ, Liang ZY, Zhang PF, Li C, Zhang JL, Zheng X and Yao YM: MACC1 expression correlates with PFKFB2 and survival in hepatocellular carcinoma. Asian Pac J Cancer Prev. 15:999–1003. 2014. View Article : Google Scholar : PubMed/NCBI
21	Gao J, Ding F, Liu Q and Yao Y: Knockdown of MACC1 expression suppressed hepatocellular carcinoma cell migration and invasion and inhibited expression of MMP2 and MMP9. Mol Cell Biochem. 376:21–32. 2013. View Article : Google Scholar
22	Shimokawa H, Uramoto H, Onitsuka T, Chundong G, Hanagiri T, Oyama T and Yasumoto K: Overexpression of MACC1 mRNA in lung adenocarcinoma is associated with postoperative recurrence. J Thorac Cardiovasc Surg. 141:895–898. 2011. View Article : Google Scholar
23	Chundong G, Uramoto H, Onitsuka T, Shimokawa H, Iwanami T, Nakagawa M, Oyama T and Tanaka F: Molecular diagnosis of MACC1 status in lung adenocarcinoma by immunohistochemical analysis. Anticancer Res. 31:1141–1145. 2011.PubMed/NCBI
24	Guo T, Kong J, Liu Y, Li Z, Xia J, Zhang Y, Zhao S, Li F, Li J and Gu C: Transcriptional activation of NANOG by YBX1 promotes lung cancer stem-like properties and metastasis. Biochem Biophys Res Commun. 487:153–159. 2017. View Article : Google Scholar : PubMed/NCBI
25	Wang Z, Cai M, Weng Y, Zhang F, Meng D, Song J, Zhou H and Xie Z: Circulating MACC1 as a novel diagnostic and prognostic biomarker for nonsmall cell lung cancer. J Cancer Res Clin Oncol. 141:1353–1361. 2015. View Article : Google Scholar
26	Yu T, Guo Z, Fan H, Song J, Liu Y, Gao Z and Wang Q: Cancer-associated fibroblasts promote non-small cell lung cancer cell invasion by upregulation of glucose-regulated protein 78 (GRP78) expression in an integrated bionic microfluidic device. Oncotarget. 7:25593–25603. 2016.PubMed/NCBI
27	Mueller MM and Fusenig NE: Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 4:839–849. 2004. View Article : Google Scholar : PubMed/NCBI
28	Friedl P, Noble PB, Walton PA, Laird DW, Chauvin PJ, Tabah RJ, Black M and Zanker KS: Migration of coordinated cell clusters in mesenchymal and epithelial cancer explants in vitro. Cancer Res. 55:4557–4560. 1995.PubMed/NCBI
29	Friedl P, Locker J, Sahai E and Segall JE: Classifying collective cancer cell invasion. Nat Cell Biol. 14:777–783. 2012. View Article : Google Scholar : PubMed/NCBI
30	Migliore C, Martin V, Leoni VP, Restivo A, Atzori L, Petrelli A, Isella C, Zorcolo L, Sarotto I, Casula G, et al: MiR-1 downregulation cooperates with MACC1 in promoting MET overexpression in human colon cancer. Clin Cancer Res. 18:737–747. 2012. View Article : Google Scholar
31	Galimi F, Torti D, Sassi F, Isella C, Corà D, Gastaldi S, Ribero D, Muratore A, Massucco P, Siatis D, et al: Genetic and expression analysis of MET, MACC1, and HGF in metastatic colorectal cancer: Response to met inhibition in patient xenografts and pathologic correlations. Clin Cancer Res. 17:3146–3156. 2011. View Article : Google Scholar : PubMed/NCBI
32	Chen S, Zong ZH, Wu DD, Sun KX, Liu BL and Zhao Y: The role of metastasis-associated in colon cancer 1 (MACC1) in endometrial carcinoma tumorigenesis and progression. Mol Carcinog. 56:1361–1371. 2017. View Article : Google Scholar
33	Zhou L, Yu L, Zhu B, Wu S, Song W, Gong X and Wang D: Metastasis-associated in colon cancer-1 and aldehyde dehydrogenase 1 are metastatic and prognostic biomarker for non-small cell lung cancer. BMC Cancer. 16:8762016. View Article : Google Scholar : PubMed/NCBI
34	Tan W, Xie X, Li L, Tang H, Ye X, Chen L, Tang W, Gao J, Pan L, Zhang X, et al: Diagnostic and prognostic value of serum MACC1 in breast cancer patients. Oncotarget. 7:84408–84415. 2016. View Article : Google Scholar : PubMed/NCBI
35	Zhang Y, Wang Z, Chen M, Peng L, Wang X, Ma Q, Ma F and Jiang B: MicroRNA-143 targets MACC1 to inhibit cell invasion and migration in colorectal cancer. Mol Cancer. 11:232012. View Article : Google Scholar : PubMed/NCBI
36	Guo T, Zhao S, Wang P, Xue X, Zhang Y, Yang M, Li N, Li Z, Xu L, Jiang L, et al: YB-1 regulates tumor growth by promoting MACC1/c-Met pathway in human lung adenocarcinoma. Oncotarget. 8:48110–48125. 2017.PubMed/NCBI
37	Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K and Sahai E: Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol. 9:1392–1400. 2007. View Article : Google Scholar : PubMed/NCBI
38	Wu X, Chen X, Zhou Q, Li P, Yu B, Li J, Qu Y, Yan J, Yu Y, Yan M, et al: Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. Cancer Lett. 335:128–135. 2013. View Article : Google Scholar : PubMed/NCBI