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Expression and Prognostic Significance of TRPV6 in the Development and Progression of Pancreatic Cancer

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Expression and Prognostic Significance of TRPV6 in the Development and Progression of Pancreatic Cancer 1432 ONCOLOGY REPORTS 39: 1432-1440, 2018 Expression and prognostic significance of TRPV6 in the development and progression of pancreatic cancer HE SONG, MING DONG, JIANPING ZHOU, WEIWEI SHENG, XIN LI and WEI GAO Department of Gastrointestinal Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China Received June 20, 2017; Accepted January 3, 2018 DOI: 10.3892/or.2018.6216 Abstract. In this study, we aimed to clarify the expression and tumor-suppressor. Nevertheless, the expression and biological biological functions of TRPV6 in human pancreatic cancer functions of TRPV6 in PC are less fully elucidated. Therefore, (PC) tissue and pancreatic cancer (PC) cell lines. TRPV6 was we analyzed the expression of TRPV6 for clinicopathological up-regulated in the primary cancer tissues from pancreatic characteristics, predicting survival in the patients, and the effect cancer (PC) patients. TRPV6 may regulate multiple proteins of silencing TRPV6 on apoptosis, proliferation, cell cycle, related to apoptosis, cell cycle and metastasis pathways. migration, invasion and chemotherapy sensitivity of PC cells, Silencing TRPV6 significantly inhibited invasion, prolifera- respectively, to gemcitabine, oxaliplatin and cisplatin. TRPV6 tion and migration and induced apoptosis and cell cycle arrest. plays a promising role in the development and progression of TRPV6 plays a promising role of an oncogene in pancreatic PC. Numb was originally discovered as a determinant of cell carcinogenesis and represents the new potential biomarker for fate (10) responsible for plenty of signal transduction pathways PC. (Hedgehog, P53), endocytosis, cell polarity determination, and ubiquitination (11), and to play an important role in cancers. Introduction Numb was recently found as a new interacting partner with TRPV6 (12). Numb inhibits activity of TRPV6 via electrostatic PC is one of the most aggressive and fatal cancers due to rapid interaction in breast cancer cells. Numb regulates Ca cation metastasis, easy recurrence, early invasion and resistance to influx via TRPV6 (13). Ca cation influx stimulated the GSK3β, conventional chemotherapy. Survival rates of PC remained AKT, MAPKinase pathway involved in TRPV6-specific medi- stagnant during the last half century (1). It was confirmatively ating cell proliferation. Silencing Numb reduced expression suggested that the early detection of PC implied a better of TRPV6 in prostate cancer cell lines (12). On the contrary, prognosis in the long-term survival (2). It is essential to search knockdown of Numb increased the TPRV6 expression in for novel biomarkers for early detection and to promote the the breast cancer cells. On the other hand, silencing TRPV6 efficiency of chemotherapy. increased the Numb expression. Numb and TRPV6 regulate the The TRPV6 channel is a calcium cation channel protein, protein stability and degradation of each other (13). Finally, we which is the major constituent of superfamily of transient observed the interaction between TRPV6 and Numb in PC cells. receptor potential (TRP) channels, further in terms of subfamily vanilloid member 6, which regulates the calcium Materials and methods homeostasis in the epithelial tissue of human organs (3). TRPV6 is overexpressed in colon cancer, breast cancer, prostate Pancreatic cancer specimens. Tumor specimens and their cancer, parathyroid cancer and thyroid cancer (3-6), however corresponding adjacent noncancerous tissues were selected decreased TRPV6 expression was observed in esophageal from patients who were pathologically confirmative of PC cancer, non-small cell lung cancer and renal cancer (7-9). during pancreatic operation in the Shenyang Medical Center Overexpression of TPPV6 in many cancers indicates the between January 2005 to January 2014. None received idea of this protein as encoded by a probable oncogene, but chemotherapy or radiotherapy in the preoperative period. the level of TRPV6 in other cancers showed a tendency of a The pathologic diagnosis and differentiation were confirmed by three independent pathologists by TNM classification, 7th edition of the UICC 2010. Fresh specimens were snap- frozen in the liquid nitrogen rapidly after operation. The Correspondence to: Dr Ming Dong, Department of Gastrointestinal study was approved by the Institutional Ethics Committee of Surgery, The First Hospital of China Medical University, Shenyang, China Medical University and written informed consent was Liaoning 110001, P.R. China obtained from the patients. E-mail: [email protected] Pancreatic cancer cell lines. We obtained BxPC-3, AsPC-1, Key words: TRPV6, pancreatic cancer, expression, progression SW1990, PANC-1 cells from the Cell Bank of the Chinese Academy of Sciences. We purchased Capan-2 cells from the song et al: prognostic significance of TRPV6 in Pancreatic Cancer 1433 American Type Culture Collection (ATCC). We maintained Table I. TRPV6 expression with clinicopathological parameters the five cell lines in growth medium supplemented with 10% from pancreatic cancer patients. fetal bovine serum and 100 µg/ml of penicillin and strepto- mycin (Hyclone, Logan, UT, USA). TRPV6 TRPV6 Parameters negative positive P-value RNA interference. We used small interfering RNA for TRPV6 (TRPV6-siRNA) and counterpart negative control (Neg.Cont) Age (year) 0.466 oligonucleotides (Shanghai GenePharma Co. Ltd.) transfected <65 20 31 with Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA). ≥65 12 13 The target sequences of oligonucleotides for the TRPV6 Sex 0.450 siRNA and Neg.Cont were as follows: TRPV6-Si1, 5'-CCAA Male 23 28 GGAGAAAGGGCUAAUTT-3'; TRPV6-Si2, 5'-CCAUAU Female 9 16 AUCUGCUGUACAUTT-3'; TRPV6-Si3, 5'-CUGCGUGG a GAUAAUCAACATT-3'. Neg.Cont: Sense, 5'-UUCUCCGAA Size (cm) 0.024 CGUGUCACGUTT-3'; Antisense, 5'-ACGUGACACGUU <2.5 20 16 CGGAGAATT-3'. ≥2.5 12 28 T Stage 0.029a Immunohistochemistry staining. Immunohistochemistry T1+T2 19 15 was performed as previously described (14). Briefly, tissue T3 13 29 sections (5 µm) were blocked with hydrogen peroxide and Lymph node 0.893 then incubated with mouse polyclonal anti-TRPV6 (1:400, N0 23 31 Invitrogen), overnight at 4˚C. As a negative control, normal IgG was used as the primary antibody at the same dilution. N1 9 13 Stained tissue sections were reviewed and scored according to Vascular permeation 0.560 Masunaga et al (15). Absent 19 29 Present 13 15 RNA preparation and quantitative real-time PCR. With CA199 (U/ml) 0.518 TRIzol reagent (Takara), total RNA was extracted, and then <37 8 14 quantitative PCR was performed with a SYBR Green II ≥37 24 30 (Takara) on a Thermal Cycler Dice Real-time System (Takara) with the following protocol: 30 sec at 95˚C followed by Perineural invasion 0.174 two-step PCR for 40 cycles of 95˚C for 5 sec and 64˚C for Absent 21 35 30 sec. Gene expression was normalized relative to its GAPDH Present 11 9 mRNA with the ∆∆CT method. The sequences of the PCR Hepatic metastasis 0.815 primers were as follows: TRPV6 forward, 5'-ATGGT Absent 21 30 GATGCGGCTCATCAGTG-3' and reverse, 5'-GTAGAAG Present 11 14 TGGCCTAGCTCCTCG-3'; GAPDH forward, 5'-CTCCTC CTGTTCGACAGTCAGC-3', and reverse 5'-CCCAATAC aP<0.05. GACCAAATCCGTT-3'. Western blotting. Pancreatic cancer tissues and pancreatic cancer cell samples were washed with ice-cold PBS and then #P04406) was used as an internal control. The protein of lysed by RIPA (Beyotime, Jiangsu, China). The lysates were interest was visualized using ECL Western blotting substrate separated in SDS-PAGE (10%). Resolved protein was trans- (Pierce, Biotechnology, Rockford, IL, USA). ferred onto a polyvinylidene difluoride (PVDF) membrane (Millipore, Bedford, MA, USA). The membranes were Cell Counting Kit-8 assay. When cell proliferation was blocked by 5% skim milk solution in TBST buffers, and were detected, at an initial density of 2,000 cells/well, cells were incubated with primary antibodies for TRPV6 (1:500 Abcam, plated in 96-well cultural dishes, Si-TRPV6 24 h after Cambridge, UK, ab63084), PCNA (1:1000, Abcam, ab29), transfection. Cells were incubated for 0, 24, 48, 72 h. CCK8 Bax (1:1000, Abcam, ab32503), Bcl-2 (1:500, Abcam, ab692), (Thiazolyl Blue) solution was added. When drug susceptibility E-cadherin (1:400, Santa Cruz Biotechnology, Santa Cruz, was detected, cells had reached the density of 5,000 cells/well, CA, USA, sc7870) MMP9 (1:400, Santa Cruz Biotechnology, 24 h after Si-TRPV6 transfection. Different concentrations of sc6840), β-catenin (1:1500, ProteinTech Group, Chicago, IL, gemcitabine, oxaliplatin or cisplatin were added, respectively, USA, 51067-2-AP), cyclin-D1 (1:1000, ProteinTech Group, and incubated for 48 h. 12363-1-AP), Numb (1:1000, Cell Signaling Technology, Danvers, MA, USA, #8650). overnight at 4˚C. PVDF Cell migration and invasion assays. After 48 h of transfec- membranes were washed in TBST and incubated with horse- tion, we adjusted the density of 2x105 cells/ml in every group. radish peroxidase-conjugated secondary antibodies (1:10000, The upper Transwell chamber (Costar; 24-well insert, pore ProteinTech Group, SA00001-15 and SA00001-1) 2 h at 37˚C. size: 8 µm) was filled with 200 µl cell suspension, and the Antibody against GAPDH (1:1000, Cell Signaling Technology, lower chamber was filled with 500 µl of medium. For the 1434 ONCOLOGY REPORTS 39: 1432-1440, 2018 Figure 1. Representative of TRPV6 expression in PC (A) and peritumor tissue (B) detected by immunostaining using anti-TRPV6 antibody (brown). (magni- fication, x200). invasion assay, polycarbonate filters coated with 50 µl Matrigel (1:9, BD Bioscience) were placed in a Transwell chamber. Cells were incubated for 24 h for the migration assay and 48 h for the invasion assay. Then, the cells on the upper surface were wiped, and the cells on the lower surface were fixed with 4% paraformaldehyde and stained with 0.1% crystal violet. The migratory cells were visualized and counted in five random visual fields per insert under an inverted microscope at x200 magnification. Cell cycle and apoptosis. Pancreatic cancer cells were treated with Si-TRPV6 or Neg.Cont oligo.
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