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Differential Expression of COL4A3 and Collagen in Upward and Downward Progressing Types of Nasopharyngeal Carcinoma

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Differential Expression of COL4A3 and Collagen in Upward and Downward Progressing Types of Nasopharyngeal Carcinoma ONCOLOGY LETTERS 21: 223, 2021 Differential expression of COL4A3 and collagen in upward and downward progressing types of nasopharyngeal carcinoma XITING YANG*, QIUJI WU*, FENGYANG WU and YAHUA ZHONG Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China Received May 4, 2020; Accepted December 21, 2020 DOI: 10.3892/ol.2021.12484 Abstract. Upward (local growth and invasion of the base of type (2.161±1.306 vs. 5.077±3.619; P<0.05). In addition, the skull), downward (distant metastasis) and mixed progressing deposition of collagen in the downward progressing type was types of nasopharyngeal carcinoma (NPC) have been identified also significantly decreased compared with that in the upward and are distinctly different with respect to clinical symptoms, progressing type (5.63±6.83 vs. 10.94±9.60; P<0.05). Kaplan- therapeutic strategies and prognosis. The present study aimed Meier analysis indicated that high expression level of COL4A3 to identify the genetic difference and collagen expression was positively associated with a favorable prognosis of head levels in the upward and downward progressing types of NPC. and neck squamous cell carcinoma (HR, 0.69; 95% CI, 0.49- Whole exon sequencing (WES) was used to detect genes 0.97; P=0.031). To confirm the role ofCOL4A3 , the expression differentially mutated between the upward and downward level of COL4A3 was knocked down using siRNA in the 5-8F progressing types of NPC. Collagen deposition in the upward cell line and the results showed that the invasion and migration and downward progressing types of NPC was determined using was significantly increased when the expression of COL4A3 Masson trichromatic staining, while the protein expression was inhibited (P<0.0001). In conclusion, the gene mutation level of COL4A3 was detected using immunohistochemistry. patterns were significantly different between the upward and Survival analysis was also performed using the Kaplan-Meier downward progressing types of NPC. In addition, the expres- Plotter database to examine the role of COL4A3 expression sion level of the COL4A3 gene was decreased in the downward level in the prognosis of head and neck squamous cell carci- progressing type, which might promote NPC metastasis noma. Knockdown of COL4A3 was performed using short through the downregulation of extracellular collagen expres- interfering (si)RNA-COL4A3 in a 5-8F NPC cell line. Reverse sion. transcription-quantitative PCR and western blot analyses were utilized to analyze the mRNA and protein expression levels of Introduction COL4A3, respectively. The roles of COL4A3 in the migration and invasion of the 5-8F cell line were examined using wound- Nasopharyngeal carcinoma (NPC) is a common malig- healing Transwell and Matrigel assays, respectively. A total nant tumor of the head and neck in southern China (1,2). of 21 genes were differentially mutated between the upward Histopathologically, unkeratinized squamous cell and undif- and downward progressing types of NPC. The COL4A3 was ferentiated carcinoma are more prevalent. According to the investigated further, as it was found to be associated with development of local invasion and distant metastasis, NPC extracellular matrix deposition and cancer metastasis. The can be categorized into three distinct types: Upward (local COL4A3 gene was markedly downregulated in the downward growth and invasion at the base of the skull), downward progressing type compared with that in the upward progressing (distant metastasis) and mixed progressing types (3,4). For the upward progressing type of NPC, local invasion is dominant, and metastasis is rare, and the prognosis is relatively good. On the other hand, up to 90% of patients with the downward progressing type of NPC develop cervical lymph node metas- Correspondence to: Professor Yahua Zhong, Department of tasis or distant metastasis, even when the primary tumor was Radiation and Medical Oncology, Hubei Key Laboratory of caught at an early stage. The extent of cervical lymph node Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, metastases is one of the most important risk factors of distant Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang, Wuhan, Hubei 430071, P.R. China metastasis (5) and the prognosis of downward progressing E-mail: [email protected] type of NPC is significantly worse compared with that in the upward progressing type (3,6). However, biomarkers associ- Key words: nasopharyngeal carcinoma, COL4A3, collagen ated with the upward and downward progressing types of NPC deposition, metastasis, molecular classification have not been fully elucidated. These two different biological behaviors of NPC have not been significantly associated with clinical characteristics, such as sex, age and pathological clas- sification. Therefore, the investigation into genetic aberration 2 YANG et al: COL4A3 FOR NASOPHARYNGEAL CARCINOMA and molecular mechanisms may lead to the identification of concentration was measured using a Bradford protein assay kit novel valuable biomarkers. (Bio-Rad Laboratories, Inc.). Then, 60 µg per well of protein Type IV collagen, one of the main components of the samples were separated using a 12% SDS-PAGE (Bio-Rad extracellular matrix and basement membrane, has been found Laboratories, Inc.) and transferred to a PVDF membrane to interact with tumor cells and regulate tumor growth, prolif- (EMD Millipore). After blocking with TBS-Tween-20 (TBST) eration, differentiation, adhesion and metastasis (7-9), which containing 5% skimmed milk for 1 h at room temperature, is important for the study of metastasis of NPC. Type IV the PVDF membrane was washed with TBST for 10 min, collagen contains three highly similar collagen precursors three times. The membrane was then incubated with primary namely, (α1)2α2(IV), α3α4α5(IV) and (α5)2α6(IV) (10). The antibodies diluted in TBST overnight at 4˚C. Antibody infor- genes, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 mation: COL4A3 (cat. no. PA5-39876, 1:500 dilution) and and COL4A6, which synthesize α1, α2, α3, α4, α5 and α6 GAPDH (cat. no. MA5-15738-D800, 1:500 dilution) antibodies peptide chains, respectively, are located in pairs on human were from Thermo Fisher Scientific, Inc. Subsequently, the chromosomes 13, 2 and X, respectively (11). In addition, membrane was washed with TBST for 10 min thrice. Following hypermethylation of the COL4A5/COL4A6 genes in colon incubation with horseradish peroxidase (HRP)-conjugated cancer led to a decrease in the expression level of the COL4A5/ goat anti-rabbit secondary antibody (cat. no. A32731; 1:10,000 COL4A6 chain and the destruction of the structural integrity dilution; Thermo Fisher Scientific, Inc.) and HRP-conjugated of the basement membrane (12). Similarly, it was found that goat anti-mouse secondary antibody (cat. no. 35518; 1:10,000 the expression level of the COL4A5/COL4A6 genes was dilution; Thermo Fisher Scientific, Inc.) for 2 h at room decreased or deleted in the invasive stage of basal cell carci- temperature, respectively. After another three washes with noma and prostate cancer (13,14). However, the role of the TBST for 10 min, the proteins were visualized using an ECL collagen-encoding genes in different types of NPC remains substrate (Pierce™ ECL Western Blotting Substrate; Thermo undetermined. Fisher Scientific, Inc.). ImageJ software version 1.48; National In the present study, whole exon sequencing (WES) Institutes of Health) was used to quantify the optical density was used to detected gene mutations associated with NPC of each protein. The relative optical density was calculated by biological behaviors and to determine the key genes associated comparing with that in GAPDH. with the invasion and metastasis potential of NPC. The role of COL4A3 gene expression and extracellular collagen, deposi- Reverse transcription-quantitative (RT-q)PCR assay. tion in both the upward and downward progressing types of Total RNA was extracted from treated cells using TRIzol® NPC, were also investigated. The inhibition of COL4A3 could (Invitrogen; Thermo Fisher Scientific, Inc.) Then, 2.0 µg total promote invasion and migration of the 5-8F NPC cell line. RNA was used for RT using a TaqMan RT kit according The present study may provide new information in identifying to the manufacturer's instructions (Applied Biosystems; novel biomarkers and establish a molecular classification of Thermo Fisher Scientific, Inc.). Subsequently, the cDNA NPC. was amplified using qPCR, in a 20 µl total reaction volume and the Go Tag Green Master Mix/Platinum SYBR Super Materials and methods mix (Invitrogen; Thermo Fisher Scientific, Inc.). qPCR was performed using the following conditions: Initial denaturation Cell culture and transfection. The human 5-8F NPC cell at 95˚C for 5 min, denaturation at 95˚C for 15 sec, 60˚C for line was donated by Sun Yat-Sen University Cancer Center 30 sec, followed by 40 cycles at 72˚C for 30 sec and 72˚C for and was cultured in RPMI-1640 medium (supplemented with 10 min. The following primers were used: COL4A3 forward, 10% fetal bovine serum, penicillin (100 U/ml) and strepto- 5'-GGACTCACGGGTTCCAAAGGT-3' and COL4A3 mycin (100 mg-ml) (all from Gibco; Thermo Fisher Scientific, reverse, 5'-CCTGCTCACCCTTAGAACCACT-3'; GAPDH Inc.) at 37˚C in a humidified incubator with 5% CO2 (Sanyo forward, 5'-CAATGACCCCTTCATTGACC-3' and GAPDH Eletcric Co., Ltd). Cells in the logarithmic growth phase were reverse, 5'-GACAAGCTTCCCGTTCTCAG-3'. GAPDH was placed in a 6-well plate and incubated until 70-90% conflu- used as the internal control. ence. Cells were transfected with specific short interfering Transwell and Matrigel assays. For the Transwell assay, 24 h (si)RNA targeting COL4A3 (designed and synthesized by following siRNA transfection, the 5-8F cell line was harvested Guangzhou Ribobio Co., Ltd.) using Lipofectamine® 2000 with trypsin and seeded into Transwell chambers (8 µm pore (Invitrogen; Thermo Fisher Scientific, Inc.) according to size; Costar; Corning, Inc.), at a density of 2x104 cells per well.
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