Laminin‑332 mediates proliferation, apoptosis, invasion, migration and epithelial‑to‑mesenchymal transition in pancreatic ductal adenocarcinoma

Huang,Caiqun; Chen,Jun

doi:10.3892/mmr.2020.11649

Laminin‑332 mediates proliferation, apoptosis, invasion, migration and epithelial‑to‑mesenchymal transition in pancreatic ductal adenocarcinoma

Authors:
- Caiqun Huang
- Jun Chen
View Affiliations

Affiliations: Department of Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, P.R. China, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, P.R. China
Published online on: November 3, 2020 https://doi.org/10.3892/mmr.2020.11649
Article Number: 11
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

The poor prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is primarily due to the invasive and metastatic behaviors of this disease. Laminin‑332 (LM‑332) is a key component of the basement membrane barrier, and is associated with tumor metastasis. The present study provides evidence towards the potential function of LM‑332 in carcinoma, indicating the distinct roles of the three LM‑332 subunits (α3, β3 and γ2) in cell proliferation, migration, invasion, apoptosis and the epithelial‑to‑mesenchymal transition (EMT) in cancer. The roles of the α3, β3 and γ2 subunits in the malignant biological behavior of PDAC were investigated in the present study. It was revealed that the α3, β3 and γ2 subunits were upregulated in PDAC. Inhibition of all LM‑332 subunits abrogated the tumorigenic outcomes, which included cell proliferation, apoptosis, invasion, migration and EMT in vitro. However, the three LM‑332 subunits had different degrees of effects on biological behavior. It was observed that LAMA3 (α3) had a stronger effect on cell proliferation, migration and invasion. In addition, LAMB3 (β3) knockdown significantly increased E‑cadherin levels and decreased vimentin levels, indicating that LAMB3 was associated with EMT. Likewise, LAMC2 (γ2) mediated proliferation, apoptosis, invasion and migration. However, small interfering (si)‑LAMC2 promoted the progression of EMT, which was the opposite effect to that of si‑LAMB3. The LM‑332 subunits (α3, β3 and γ2) may be novel therapeutic targets of PDAC in the future.

View Figures

View References

1	Fan CS, Chen LL, Hsu TA, Chen CC, Chua KV, Li CP and Huang TS: Endothelial-mesenchymal transition harnesses HSP90α-secreting M2-macrophages to exacerbate pancreatic ductal adenocarcinoma. J Hematol Oncol. 12:1382019. View Article : Google Scholar : PubMed/NCBI
2	Erickson LA: Pancreatic ductal adenocarcinoma. Mayo Clin Proc. 92:1461–1462. 2017. View Article : Google Scholar : PubMed/NCBI
3	Li JT, Wang YP, Yin M and Lei QY: Metabolism remodeling in pancreatic ductal adenocarcinoma. Cell Stress. 3:361–368. 2019. View Article : Google Scholar : PubMed/NCBI
4	Ayres Pereira M and Chio IC: Metastasis in pancreatic ductal adenocarcinoma: Current standing and methodologies. Genes (Basel). 11:112019. View Article : Google Scholar
5	Li B, Liu B, Zhang X, Liu H and He L: KIF18B promotes the proliferation of pancreatic ductal adenocarcinoma via activating the expression of CDCA8. J Cell Physiol. 235:4227–4238. 2020. View Article : Google Scholar : PubMed/NCBI
6	Oh KH, Choi J, Woo JS, Baek SK, Jung KY, Koh MJ, Kim YS and Kwon SY: Role of laminin 332 in lymph node metastasis of papillary thyroid carcinoma. Auris Nasus Larynx. 44:729–734. 2017. View Article : Google Scholar : PubMed/NCBI
7	Kang SG, Ha YR, Ko YH, Kang SH, Joo KJ, Cho HY, Park HS, Kim CH, Kwon SY, Kim JJ, et al: Effect of laminin 332 on motility and invasion in bladder cancer. Kaohsiung J Med Sci. 29:422–429. 2013. View Article : Google Scholar : PubMed/NCBI
8	Carpenter PM, Sivadas P, Hua SS, Xiao C, Gutierrez AB, Ngo T and Gershon PD: Migration of breast cancer cell lines in response to pulmonary laminin 332. Cancer Med. 6:220–234. 2017. View Article : Google Scholar : PubMed/NCBI
9	Chiorean R, Danescu S, Virtic O, Mustafa MB, Baican A, Lischka A, Hashimoto T, Kariya Y, Koch M and Sitaru C: Molecular diagnosis of anti-laminin 332 (epiligrin) mucous membrane pemphigoid. Orphanet J Rare Dis. 13:1112018. View Article : Google Scholar : PubMed/NCBI
10	Rousselle P and Beck K: Laminin 332 processing impacts cellular behavior. Cell Adhes Migr. 7:122–134. 2013. View Article : Google Scholar
11	Carpenter PM, Ziogas A, Markham EM, Cantillep AS, Yan R and Anton-Culver H: Laminin 332 expression and prognosis in breast cancer. Hum Pathol. 82:289–296. 2018. View Article : Google Scholar : PubMed/NCBI
12	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI
13	De Craene B and Berx G: Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 13:97–110. 2013. View Article : Google Scholar : PubMed/NCBI
14	Wrighton KH: Cell migration: EMT promotes contact inhibition of locomotion. Nat Rev Mol Cell Biol. 16:5182015. View Article : Google Scholar : PubMed/NCBI
15	Lee J, Choi JH and Joo CK: TGF-β1 regulates cell fate during epithelial-mesenchymal transition by upregulating survivin. Cell Death Dis. 4:e7142013. View Article : Google Scholar : PubMed/NCBI
16	Kenda Suster N, Smrkolj S and Virant-Klun I: Putative stem cells and epithelial-mesenchymal transition revealed in sections of ovarian tumor in patients with serous ovarian carcinoma using immunohistochemistry for vimentin and pluripotency-related markers. J Ovarian Res. 10:112017. View Article : Google Scholar : PubMed/NCBI
17	Chen J, Zhang H, Luo J, Wu X, Li X, Zhao X, Zhou D and Yu S: Overexpression of α3, β3 and γ2 chains of laminin-332 is associated with poor prognosis in pancreatic ductal adenocarcinoma. Oncol Lett. 16:199–210. 2018.PubMed/NCBI
18	Murakami S, Shahbazian D, Surana R, Zhang W, Chen H, Graham GT, White SM, Weiner LM and Yi C: Yes-associated protein mediates immune reprogramming in pancreatic ductal adenocarcinoma. Oncogene. 36:1232–1244. 2017. View Article : Google Scholar : PubMed/NCBI
19	Pandey R, Zhou M, Islam S, Chen B, Barker NK, Langlais P, Srivastava A, Luo M, Cooke LS, Weterings E, et al: Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target. Sci Rep. 9:183472019. View Article : Google Scholar : PubMed/NCBI
20	Chen J, Wang W, Wei J, Zhou D, Zhao X, Song W, Sun Q, Huang P and Zheng S: Overexpression of β3 chains of laminin-332 is associated with clinicopathologic features and decreased survival in patients with pancreatic adenocarcinoma. Appl Immunohistochem Mol Morphol. 23:516–521. 2015. View Article : Google Scholar : PubMed/NCBI
21	Gupta R, Amanam I and Chung V: Current and future therapies for advanced pancreatic cancer. J Surg Oncol. 116:25–34. 2017. View Article : Google Scholar : PubMed/NCBI
22	Kligys K, Wu Y, Hamill KJ, Lewandowski KT, Hopkinson SB, Budinger GR and Jones JC: Laminin-332 and α3β1 integrin-supported migration of bronchial epithelial cells is modulated by fibronectin. Am J Respir Cell Mol Biol. 49:731–740. 2013. View Article : Google Scholar : PubMed/NCBI
23	Erdogan B and Webb DJ: Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans. 45:229–236. 2017. View Article : Google Scholar : PubMed/NCBI
24	Lugano R, Vemuri K, Yu D, Bergqvist M, Smits A, Essand M, Johansson S, Dejana E and Dimberg A: CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis. J Clin Invest. 128:3280–3297. 2018. View Article : Google Scholar : PubMed/NCBI
25	Kamoshida G, Ogawa T, Oyanagi J, Sato H, Komiya E, Higashi S, Miyazaki K and Tsuji T: Modulation of matrix metalloproteinase-9 secretion from tumor-associated macrophage-like cells by proteolytically processed laminin-332 (laminin-5). Clin Exp Metastasis. 31:285–291. 2014. View Article : Google Scholar : PubMed/NCBI
26	Kariya Y, Sato H, Katou N, Kariya Y and Miyazaki K: Polymerized laminin-332 matrix supports rapid and tight adhesion of keratinocytes, suppressing cell migration. PLoS One. 7:e355462012. View Article : Google Scholar : PubMed/NCBI
27	Guess CM and Quaranta V: Defining the role of laminin-332 in carcinoma. Matrix Biol. 28:445–455. 2009. View Article : Google Scholar : PubMed/NCBI
28	Zhang J, Wang H, Wang Y, Dong W, Jiang Z and Yang G: Substrate-mediated gene transduction of LAMA3 for promoting biological sealing between titanium surface and gingival epithelium. Colloids Surf B Biointerfaces. 161:314–323. 2018. View Article : Google Scholar : PubMed/NCBI
29	Fuentes I, Campos M, Repetto G, Morandé P, Yubero MJ, Gonzalez S, Klausegger A, Schnitzhofer P, Pohla-Gubo G, Bauer J, et al: Molecular epidemiology of junctional epidermolysis bullosa: Discovery of novel and frequent LAMB3 mutations in Chilean patients with diagnostic significance. Br J Dermatol. 176:1090–1092. 2017. View Article : Google Scholar : PubMed/NCBI
30	Mayer B, Silló P, Mazán M, Pintér D, Medvecz M, Has C, Castiglia D, Petit F, Charlesworth A, Hatvani Z, et al: A unique LAMB3 splice-site mutation with founder effect from the Balkans causes lethal epidermolysis bullosa in several European countries. Br J Dermatol. 175:721–727. 2016. View Article : Google Scholar : PubMed/NCBI
31	Calaluce R, Bearss DJ, Barrera J, Zhao Y, Han H, Beck SK, McDaniel K and Nagle RB: Laminin-5 beta3A expression in LNCaP human prostate carcinoma cells increases cell migration and tumorigenicity. Neoplasia. 6:468–479. 2004. View Article : Google Scholar : PubMed/NCBI
32	Jung SN, Lim HS, Liu L, Chang JW, Lim YC, Rha KS and Koo BS: LAMB3 mediates metastatic tumor behavior in papillary thyroid cancer by regulating c-MET/Akt signals. Sci Rep. 8:27182018. View Article : Google Scholar : PubMed/NCBI
33	Zhang H, Pan YZ, Cheung M, Cao M, Yu C, Chen L, Zhan L, He ZW and Sun CY: LAMB3 mediates apoptotic, proliferative, invasive, and metastatic behaviors in pancreatic cancer by regulating the PI3K/Akt signaling pathway. Cell Death Dis. 10:2302019. View Article : Google Scholar : PubMed/NCBI
34	Kobayashi T, Masaki T, Nozaki E, Sugiyama M, Nagashima F, Furuse J, Onishi H, Watanabe T and Ohkura Y: Microarray analysis of gene expression at the tumor front of colon cancer. Anticancer Res. 35:6577–6581. 2015.PubMed/NCBI
35	Moon YW, Rao G, Kim JJ, Shim HS, Park KS, An SS, Kim B, Steeg PS, Sarfaraz S, Changwoo Lee L, et al: LAMC2 enhances the metastatic potential of lung adenocarcinoma. Cell Death Differ. 22:1341–1352. 2015. View Article : Google Scholar : PubMed/NCBI
36	Sato H, Higashi S and Miyazaki K: Amino-terminal fragments of laminin γ2 chain stimulate migration of metastatic breast cancer cells by interacting with CD44. Clin Exp Metastasis. 32:405–415. 2015. View Article : Google Scholar : PubMed/NCBI
37	Crha K, Ventruba P, Žáková J, Ješeta M, Pilka R, Vodička J and Serpa P: The role of mesenchymal-epithelial transition in endometrial function and receptivity. Ceska Gynekol. 84:371–375. 2019.PubMed/NCBI
38	Kar R, Jha NK, Jha SK, Sharma A, Dholpuria S, Asthana N, Chaurasiya K, Singh VK, Burgee S and Nand P: A ‘NOTCH’ deeper into the epithelial-to-mesenchymal transition (EMT) program in breast cancer. Genes (Basel). 10:102019. View Article : Google Scholar
39	Peng YS, Syu JP, Wang SD, Pan PC and Kung HN: BSA-bounded p-cresyl sulfate potentiates the malignancy of bladder carcinoma by triggering cell migration and EMT through the ROS/Src/FAK signaling pathway. Cell Biol Toxicol. 36:287–300. 2020. View Article : Google Scholar : PubMed/NCBI
40	Hanrahan K, O'Neill A, Prencipe M, Bugler J, Murphy L, Fabre A, Puhr M, Culig Z, Murphy K and Watson RW: The role of epithelial-mesenchymal transition drivers ZEB1 and ZEB2 in mediating docetaxel-resistant prostate cancer. Mol Oncol. 11:251–265. 2017. View Article : Google Scholar : PubMed/NCBI
41	Li L, Liu J, Xue H, Li C, Liu Q, Zhou Y, Wang T, Wang H, Qian H and Wen T: A TGF-beta-MTA1-SOX4-EZH2 signaling axis drives epithelial-mesenchymal transition in tumor metastasis. Oncogene. 39:2125–2139. 2020. View Article : Google Scholar : PubMed/NCBI