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| 1 | Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib显示文摘Background:Cancer-associated fibroblasts(CAFs)play an important role in the induction of chemo-resistance.This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma(HCC).Methods:We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues,respectively,to identify key molecules that might induce resistance to TKIs.We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms.The associations of plasma secreted phosphoprotein 1(SPP1)expression levels before sorafenib/lenvatinib treatment with progression-free survival(PFS)and overall survival(OS)of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis.Results:Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance.SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo.CAF-derived SPP1 activated rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)through the integrin-protein kinase C-alpha(PKCα)signaling pathway and promoted epithelial-to-mesenchymal transition(EMT).A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS(P=0.026)and OS(P=0.047)in patients with advanced HCC after TKI treatment.Conclusions:CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion.Its inhibition represents a promising therapeutic strategy against TKI resistance inHCC.Moreover,plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction. | JungWoo Eun Jung Hwan Yoon Hye Ri Ahn Seokhwi Kim Young Bae Kim Su Bin Lim Won Park TaeWook Kang Geum Ok Baek Moon Gyeong Yoon Ju A Son Ji HyangWeon Soon Sun Kim Hyo Jung Cho Jae Youn Cheong | 2023 | Cancer Communications2023，43，4： | 2 |
| 2 | Cancer surveillance series: recent trends in childhood cancer incidence and mortality in the United States 显示文摘 | Linet S Ries L A Smith M A | 1999 | J Nad Cancer Inst1999，91，12： | 1 |
| 3 | Inherent Limitations of Vol- umetric Solar Receivers 显示文摘 | Kribus A Ries H Spirkl W | 1996 | Journal of Soalr Energy En- gineering1996，118，： | 1 |
| 4 | BAG-1 prevents stress-induced long-term growth inhibition in breast cancer cells via a chaperone-dependent pathway显示文摘 | Townsend PA Cutress RI Sharp A | 2003 | Cancer Res2003，63，14： | 1 |
| 5 | Neuroprotection against excitotoxic brain injury in mice after ovarian steroid depletion 显示文摘 | Schauwecker PE Wood RI Lorenzana A | 2009 | Brain Res2009，1265，： | 1 |
| 6 | Pulmonary re-habilitation: Joint ACCP/ A AC VPR evidence-based clin-ical practice guidelines显示文摘 | Ries A L Bauldoff G S Carlin B W | 2007 | Chest2007，131，1： | 1 |
| 7 | Diuretic resistance and me- chanical ventilation in decompensated cor pulmonale: Successful treatment by slow continuous ultrafiltration 显示文摘 | Ries W Schenzer A Liiken J | 2012 | Der Internist2012，53，8： | 1 |
| 8 | How to Position Your Product 显示文摘 | Ries A Trout J | 1972 | Advertising Age1972，43，8： | 1 |
| 9 | Study of humic-like substances in fog and interstitial aerosol by size-exclusion chromatography and capillary electrophoresis显示文摘 | Z Krivácsy Gy Kiss B Varga I Galambos Zs Sárvári A Gelencsér á Molnár S Fuzzi M.C Facchini S Zappoli A Andracchio T Alsberg H.C Hansson L Persson | 2000 | Atmospheric Environment2000，，25： | 1 |
| 10 | Delayed engraftment of 4-hydroperoxycyclophosphamide-purged autologous bone marrow after induction treatment containing mitoxantrone for acute myelogenous leukemia显示文摘 | RUGO H S RIES C A | 1996 | Bone Marrow Transplant1996，17，1： | 1 |
| 11 | A nonlinear calcification response to C02-induced ocean acidification by the coral Oeulina arhuscula 显示文摘 | Ries J Cohen A Mccorkle D | 2010 | CoralReefs2010，29，3： | 1 |
| 12 | Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control显示文摘 | Jemal A Thun MJ Ries LA | 2008 | J Natl Cancer Inst2008，100，23： | 1 |
| 13 | Estimation of biomass in aneotropical forest of French Guiana:spatial and temporal variability显示文摘 | Chave J Riéra B Dubois M A | 2001 | Journal ofTropical Ecology2001，17，： | 1 |
| 14 | The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription显示文摘 | Cutress RI Townsend PA Sharp A | 2003 | Oncogene2003，22，32： | 1 |
| 15 | High-throughput proteomic analysis of human infiltrating ductal carcinoma of the breast 显示文摘 | Somiari RI Sullivan A Russell S | 2003 | Proteomics2003，3，10： | 1 |
| 16 | A novel hydrogen-evolving photocatalyst InVO4 active under visible light irradiation 显示文摘 | YE J H ZOU Z OSHIK/RI M MATSUSHITA A SHIMODA M IMAI M SHISHIDO T | 2002 | Chem Phys Lett2002，356，： | 1 |
| 17 | Hyperkalemic cardiac arrest after cardiopulmonary bypass in a child with unsuspected duchenne muscular dystrophy 显示文摘 | Nathan A Ganesh A Godinez RI | 2005 | Anesth Analg2005，100，： | 1 |
| 18 | Prevalence of dry eye in Japanese eye centers 显示文摘 | Hikichi T Yoshida A Fukui Y Hamano T Ri M Araki K | 1995 | Graefe Arch Clin Exp Ophthalmol1995，233，9： | 1 |
| 19 | Placental α-microglobulin-I to detect uncertain rupture of membranes in a European cohort of pregnancies显示文摘 | Birkenmaier A Ries JJ Kuhle J | 2012 | Arch Gynecol Obstet2012，285，1： | 1 |
| 20 | Cancer statistics,2008显示文摘 | Jemal A Siegel Ri Ward E | 2008 | CA Cancer J Clin2008，58，2： | 1 |
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