• 1.上海交通大學(xué)醫(yī)學(xué)院附屬第三人民醫(yī)院普外一科(上海 201999);;
  • 2.安徽省蚌埠醫(yī)學(xué)院研究生部(安徽蚌埠 233030);

目的  總結(jié)膽囊癌相關(guān)耐藥基因及其靶向治療的研究進(jìn)展。
方法  收集國內(nèi)外近年來有關(guān)膽囊癌相關(guān)耐藥基因及其靶向治療的文獻(xiàn)并作綜述。
結(jié)果  膽囊癌化療耐藥的機(jī)理主要涉及溶酶體蛋白跨膜β4抗體(LAP-TM4B)基因、核因子E2相關(guān)因子2 (Nrf2)基因及腫瘤干細(xì)胞(CSCs)。膽囊癌治療的基因靶點(diǎn)主要有LAPTM4B、Nemo樣激酶(NLK)、組織因子途徑抑制物-2 (TFPI-2)、血管內(nèi)皮生長因子-D (VEGF-D)、表皮生長因子受體(EGFR)及黑色素瘤分化相關(guān)基因-7/白介素-24 (mda-7/IL-24)基因。
結(jié)論  膽囊癌相關(guān)耐藥基因及其靶向治療的研究均取得了一定的進(jìn)展,拓寬了膽囊癌的傳統(tǒng)治療理念。

引用本文: 俞遠(yuǎn)林,姜波健,俞繼衛(wèi). 膽囊癌相關(guān)耐藥基因及靶向治療的研究進(jìn)展△. 中國普外基礎(chǔ)與臨床雜志, 2013, 20(12): 1432-1436. doi: 復(fù)制

1. Kokudo N, Makuuchi M, Natori T, et al. Strategies for surgical treatment of gallbladder carcinoma based on information available before resection[J]. Arch Surg, 2003, 138(7):741-750.
2. Goldin RD, Roa JC. Gallbladder cancer:a morphological and molecular update[J]. Histopathology, 2009, 55(2):218-229.
3. Rai R, Tewari M, Kumar M, et al. p53:its alteration and gallbladder cancer[J]. Eur J Cancer Prev, 2011, 20(2):77-85.
4. Alsheyab FM, Ziadeh MT, Bani-Hani KE. Expression of p21 and p27 in gallbladder cancer[J]. Saudi Med J, 2007, 28(5):683-687.
5. Moon WS, Park HS, Lee H, et al. Co-expression of cox-2, C-metand beta-catenin in cells forming invasive front of gallbladder cancer[J]. Cancer Res Treat, 2005, 37(3):171-176.
6. Kim YW, Huh SH, Park YK, et al. Expression of the c-erb-B2and p53 protein in gallbladder carcinomas[J]. Oncol Rep, 2001, 8(5):1127-1132.
7. Rupesh P, Manoj P, Vijay Kumar S. Biomarkers in carcinoma of the gallbladder[J]. Expert Opin Med Diagn, 2008, 2(5):511-526.
8. Boutros C, Gary M, Baldwin K, et al. Gallbladder cancer:past, present and an uncertain future[J]. Surg Oncol, 2012, 21(4):183-191.
9. Andrén-Sandberg A. Molecular biology of gallbladder cancer:potential clinical implications[J]. N Am J Med Sci, 2012, 4(10):435-441.
10. Zhai G, Yan K, Ji X, et al. LAPTM4B allele*2 is a marker of poor prognosis for gallbladder carcinoma[J]. PLoS One, 2012, 7(9):e45290.
11. Meng F, Li H, Zhou R, et al. LAPTM4B gene polymorphism and endometrial carcinoma risk and prognosis[J]. Biomarkers, 2013, 18(2):136-143.
12. Meng FL, Song HT, Luo C, et al. Correlation of LAPTM4B polymorphisms with cervical carcinoma[J]. Cancer, 2011, 117(12):2652-2658.
13. Zhou L, He XD, Yu JC, et al. Overexpression of LAPTM4B-35 attenuates epirubucin-induced apoptosis of gallbladder carcinoma GBC-SD cells[J]. Surgery, 2011, 150(1):25-31.
14. Lau A, Villeneuve NF, Sun Z, et al. Dual roles of Nrf2 in cancer[J]. Pharmacol Res, 2008, 58(5-6):262-270.
15. Zhang L, Wang N, Zhou S, et al. Propofol induces proliferationand invasion of gallbladder cancer cells through activation of Nrf2[J]. J Exp Clin Cancer Res, 2012, 31(1):66-74.
16. Shibata T, Kokubu A, Gotoh M, et al. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer[J]. Gastroenterology, 2008, 135(4):1358-1368.
17. Wang J, Zhang M, Zhang L, et al. Correlation of Nrf2, HO-1, and MRP3 in gallbladder cancer and their relationships to clinicopathologic features and survival[J]. J Surg Res, 2010, 164(1):e99-e105.
18. Bonnet D, Dick JE. Human acute myeloid leukemia is organizedas a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med, 1997, 3(7):730-737.
19. 張鵬, 俞繼衛(wèi), 姜波健. 腫瘤干細(xì)胞與胃腸道癌發(fā)生和轉(zhuǎn)移[J].中國普外基礎(chǔ)與臨床雜志, 2009, 16(1):81-84.
20. Bomken S, Fiser K, Heidenreich O, et al. Understanding the cancer stem cell[J]. Br J Cancer, 2010, 103(4):439-445.
21. 陸瑞祺, 吳巨鋼, 周國才, 等. 胃癌CD133陽性細(xì)胞的純化及其生物學(xué)特性研究[J]. 中國普外基礎(chǔ)與臨床雜志, 2011, 18(12):1265-1270.
22. Zhang Z, Zhu F, Xiao L, et al. Side population cells in human gallbladder cancer cell line GBC-SD regulated by TGF-β-induced epithelial-mesenchymal transition[J]. J Huazhong Univ Sci Technolog Med Sci, 2011, 31(6):749-755.
23. 胡均, 李健, 劉文松, 等. 人膽囊癌GBC-SD細(xì)胞系中干細(xì)胞樣SP細(xì)胞群的分離及其ABCG2的表達(dá)[J]. 華中科技大學(xué)學(xué)報(bào):醫(yī)學(xué)版, 2008, 37(2):200-203.
24. Shi C, Tian R, Wang M, et al. CD44+ CD133+ population exhi-bits cancer stem cell-like characteristics in human gallbladder carc-inoma[J]. Cancer Biol Ther, 2010, 10(11):1182-1190.
25. Sachlos E, Risueño RM, Laronde S, et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells[J]. Cell, 2012, 149(6):1284-1297.
26. Maugeri-Saccà M, Vigneri P, De Maria R. Cancer stem cells and chemosensitivity[J]. Clin Cancer Res, 2011, 17(15):4942-4947.
27. Li XX, Wang J, Wang HL, et al. Characterization of cancer ste-mlike cells derived from a side population of a human gallbladder carcinoma cell line, SGC-996[J]. Biochem Biophys Res Commun, 2012, 419(4):728-734.
28. Yang H, Zhai G, Ji X, et al. Correlation of LAPTM4B polymorp-hisms with gallbladder carcinoma susceptibility in Chinese patients[J]. Med Oncol, 2012, 29(4):2809-2813.
29. Yasuda J, Tsuchiya A, Yamada T, et al. Nemo-like kinase inducesapoptosis in DLD-1 human colon cancer cells[J]. Biochem Biop-hys Res Commun, 2003, 308(2):227-233.
30. Jung KH, Kim JK, Noh JH, et al. Targeted disruption of Nemo-like kinase inhibits tumor cell growth by simultaneous suppression of cyclin D1 and CDK2 in human hepatocellular carcinoma[J]. J Cell Biochem, 2010, 110(3):687-696.
31. Tan Z, Li M, Wu W, et al. NLK is a key regulator of proliferationand migration in gallbladder carcinoma cells[J]. Mol Cell Biochem, 2012, 369(1-2):27-33.
32. Qin Y, Zhang S, Gong W, et al. Adenovirus-mediated gene transfer of tissue factor pathway inhibitor-2 inhibits gallbladder carcinoma growth in vitro and in vivo[J]. Cancer Sci, 2012, 103(4):723-730.
33. 蔣雷, 陳燕凌, 余菲菲, 等. 膽囊癌組織中血管內(nèi)皮生長因子C和D的表達(dá)及其與淋巴管和血管生成的關(guān)系[J]. 中華腫瘤雜志, 2010, 32(3):190-195.
34. Lin W, Jiang L, Chen Y, et al. Vascular endothelial growth factor-D promotes growth, lymphangiogenesis and lymphatic metastasis in gallbladder cancer[J]. Cancer Lett, 2012, 314(2):127-136.
35. Pignochino Y, Sarotto I, Peraldo-Neia C, et al. Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabinein biliary tract and gallbladder carcinomas[J]. BMC Cancer, 2010,10(1):631.
36. Jia J, Li S, Gong W, et al. mda-7/IL-24 induces apoptosis in human GBC-SD gallbladder carcinoma cells via mitochondrial apoptotic pathway[J]. Oncol Rep, 2011, 25(1):195-201.
37. Zhang JT, Fan YZ, Chen CQ, et al. Norcantharidin:a potentialantiangiogenic agent for gallbladder cancers in vitro and in vivo[J].Int J Oncol, 2012, 40(5):1501-1514.
38. 秦一雨, 李濟(jì)宇, 李松崗, 等. 生長抑素逆轉(zhuǎn)膽囊癌細(xì)胞株耐藥性的作用研究[J]. 中華外科雜志, 2008, 46(5):381-383.
39. Wang JW, Peng SY, Li JT, et al. Identification of metastasis-ass-ociated proteins involved in gallbladder carcinoma metastasis by proteomic analysis and functional exploration of chloride intracellular channel 1[J]. Cancer Lett, 2009, 281(1):71-81.
40. Zhang Z, Wang X, Wu W, et al. Effects of matrine on proliferation and apoptosis in gallbladder carcinoma cells (GBC-SD)[J]. Phytother Res, 2012, 26(6):932-937.
  1. 1. Kokudo N, Makuuchi M, Natori T, et al. Strategies for surgical treatment of gallbladder carcinoma based on information available before resection[J]. Arch Surg, 2003, 138(7):741-750.
  2. 2. Goldin RD, Roa JC. Gallbladder cancer:a morphological and molecular update[J]. Histopathology, 2009, 55(2):218-229.
  3. 3. Rai R, Tewari M, Kumar M, et al. p53:its alteration and gallbladder cancer[J]. Eur J Cancer Prev, 2011, 20(2):77-85.
  4. 4. Alsheyab FM, Ziadeh MT, Bani-Hani KE. Expression of p21 and p27 in gallbladder cancer[J]. Saudi Med J, 2007, 28(5):683-687.
  5. 5. Moon WS, Park HS, Lee H, et al. Co-expression of cox-2, C-metand beta-catenin in cells forming invasive front of gallbladder cancer[J]. Cancer Res Treat, 2005, 37(3):171-176.
  6. 6. Kim YW, Huh SH, Park YK, et al. Expression of the c-erb-B2and p53 protein in gallbladder carcinomas[J]. Oncol Rep, 2001, 8(5):1127-1132.
  7. 7. Rupesh P, Manoj P, Vijay Kumar S. Biomarkers in carcinoma of the gallbladder[J]. Expert Opin Med Diagn, 2008, 2(5):511-526.
  8. 8. Boutros C, Gary M, Baldwin K, et al. Gallbladder cancer:past, present and an uncertain future[J]. Surg Oncol, 2012, 21(4):183-191.
  9. 9. Andrén-Sandberg A. Molecular biology of gallbladder cancer:potential clinical implications[J]. N Am J Med Sci, 2012, 4(10):435-441.
  10. 10. Zhai G, Yan K, Ji X, et al. LAPTM4B allele*2 is a marker of poor prognosis for gallbladder carcinoma[J]. PLoS One, 2012, 7(9):e45290.
  11. 11. Meng F, Li H, Zhou R, et al. LAPTM4B gene polymorphism and endometrial carcinoma risk and prognosis[J]. Biomarkers, 2013, 18(2):136-143.
  12. 12. Meng FL, Song HT, Luo C, et al. Correlation of LAPTM4B polymorphisms with cervical carcinoma[J]. Cancer, 2011, 117(12):2652-2658.
  13. 13. Zhou L, He XD, Yu JC, et al. Overexpression of LAPTM4B-35 attenuates epirubucin-induced apoptosis of gallbladder carcinoma GBC-SD cells[J]. Surgery, 2011, 150(1):25-31.
  14. 14. Lau A, Villeneuve NF, Sun Z, et al. Dual roles of Nrf2 in cancer[J]. Pharmacol Res, 2008, 58(5-6):262-270.
  15. 15. Zhang L, Wang N, Zhou S, et al. Propofol induces proliferationand invasion of gallbladder cancer cells through activation of Nrf2[J]. J Exp Clin Cancer Res, 2012, 31(1):66-74.
  16. 16. Shibata T, Kokubu A, Gotoh M, et al. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer[J]. Gastroenterology, 2008, 135(4):1358-1368.
  17. 17. Wang J, Zhang M, Zhang L, et al. Correlation of Nrf2, HO-1, and MRP3 in gallbladder cancer and their relationships to clinicopathologic features and survival[J]. J Surg Res, 2010, 164(1):e99-e105.
  18. 18. Bonnet D, Dick JE. Human acute myeloid leukemia is organizedas a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med, 1997, 3(7):730-737.
  19. 19. 張鵬, 俞繼衛(wèi), 姜波健. 腫瘤干細(xì)胞與胃腸道癌發(fā)生和轉(zhuǎn)移[J].中國普外基礎(chǔ)與臨床雜志, 2009, 16(1):81-84.
  20. 20. Bomken S, Fiser K, Heidenreich O, et al. Understanding the cancer stem cell[J]. Br J Cancer, 2010, 103(4):439-445.
  21. 21. 陸瑞祺, 吳巨鋼, 周國才, 等. 胃癌CD133陽性細(xì)胞的純化及其生物學(xué)特性研究[J]. 中國普外基礎(chǔ)與臨床雜志, 2011, 18(12):1265-1270.
  22. 22. Zhang Z, Zhu F, Xiao L, et al. Side population cells in human gallbladder cancer cell line GBC-SD regulated by TGF-β-induced epithelial-mesenchymal transition[J]. J Huazhong Univ Sci Technolog Med Sci, 2011, 31(6):749-755.
  23. 23. 胡均, 李健, 劉文松, 等. 人膽囊癌GBC-SD細(xì)胞系中干細(xì)胞樣SP細(xì)胞群的分離及其ABCG2的表達(dá)[J]. 華中科技大學(xué)學(xué)報(bào):醫(yī)學(xué)版, 2008, 37(2):200-203.
  24. 24. Shi C, Tian R, Wang M, et al. CD44+ CD133+ population exhi-bits cancer stem cell-like characteristics in human gallbladder carc-inoma[J]. Cancer Biol Ther, 2010, 10(11):1182-1190.
  25. 25. Sachlos E, Risueño RM, Laronde S, et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells[J]. Cell, 2012, 149(6):1284-1297.
  26. 26. Maugeri-Saccà M, Vigneri P, De Maria R. Cancer stem cells and chemosensitivity[J]. Clin Cancer Res, 2011, 17(15):4942-4947.
  27. 27. Li XX, Wang J, Wang HL, et al. Characterization of cancer ste-mlike cells derived from a side population of a human gallbladder carcinoma cell line, SGC-996[J]. Biochem Biophys Res Commun, 2012, 419(4):728-734.
  28. 28. Yang H, Zhai G, Ji X, et al. Correlation of LAPTM4B polymorp-hisms with gallbladder carcinoma susceptibility in Chinese patients[J]. Med Oncol, 2012, 29(4):2809-2813.
  29. 29. Yasuda J, Tsuchiya A, Yamada T, et al. Nemo-like kinase inducesapoptosis in DLD-1 human colon cancer cells[J]. Biochem Biop-hys Res Commun, 2003, 308(2):227-233.
  30. 30. Jung KH, Kim JK, Noh JH, et al. Targeted disruption of Nemo-like kinase inhibits tumor cell growth by simultaneous suppression of cyclin D1 and CDK2 in human hepatocellular carcinoma[J]. J Cell Biochem, 2010, 110(3):687-696.
  31. 31. Tan Z, Li M, Wu W, et al. NLK is a key regulator of proliferationand migration in gallbladder carcinoma cells[J]. Mol Cell Biochem, 2012, 369(1-2):27-33.
  32. 32. Qin Y, Zhang S, Gong W, et al. Adenovirus-mediated gene transfer of tissue factor pathway inhibitor-2 inhibits gallbladder carcinoma growth in vitro and in vivo[J]. Cancer Sci, 2012, 103(4):723-730.
  33. 33. 蔣雷, 陳燕凌, 余菲菲, 等. 膽囊癌組織中血管內(nèi)皮生長因子C和D的表達(dá)及其與淋巴管和血管生成的關(guān)系[J]. 中華腫瘤雜志, 2010, 32(3):190-195.
  34. 34. Lin W, Jiang L, Chen Y, et al. Vascular endothelial growth factor-D promotes growth, lymphangiogenesis and lymphatic metastasis in gallbladder cancer[J]. Cancer Lett, 2012, 314(2):127-136.
  35. 35. Pignochino Y, Sarotto I, Peraldo-Neia C, et al. Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabinein biliary tract and gallbladder carcinomas[J]. BMC Cancer, 2010,10(1):631.
  36. 36. Jia J, Li S, Gong W, et al. mda-7/IL-24 induces apoptosis in human GBC-SD gallbladder carcinoma cells via mitochondrial apoptotic pathway[J]. Oncol Rep, 2011, 25(1):195-201.
  37. 37. Zhang JT, Fan YZ, Chen CQ, et al. Norcantharidin:a potentialantiangiogenic agent for gallbladder cancers in vitro and in vivo[J].Int J Oncol, 2012, 40(5):1501-1514.
  38. 38. 秦一雨, 李濟(jì)宇, 李松崗, 等. 生長抑素逆轉(zhuǎn)膽囊癌細(xì)胞株耐藥性的作用研究[J]. 中華外科雜志, 2008, 46(5):381-383.
  39. 39. Wang JW, Peng SY, Li JT, et al. Identification of metastasis-ass-ociated proteins involved in gallbladder carcinoma metastasis by proteomic analysis and functional exploration of chloride intracellular channel 1[J]. Cancer Lett, 2009, 281(1):71-81.
  40. 40. Zhang Z, Wang X, Wu W, et al. Effects of matrine on proliferation and apoptosis in gallbladder carcinoma cells (GBC-SD)[J]. Phytother Res, 2012, 26(6):932-937.