Relationship between liver regeneration after ALPPS and endoplasmic reticulum stress IRE1α-XBP1 pathway_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

GONG Qi , XU Feng , ZHAO Liang ,  DAI Chaoliu

Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, P. R. China;

Corresponding author：

DAI Chaoliu, Email: daicl@sj-hospital.org

Keywords：

liver regeneration; endoplasmic reticulum stress; proliferation; associating liver partition and portal vein ligation for staged hepatectomy; X-box binding protein 1; inositol-requiring enzyme 1α

DOI：

10.7507/1007-9424.201905046

Video：

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Objective To investigate the role of endoplasmic reticulum stress in liver regeneration after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS).Methods Seventy-two C57bl/6 mice were randomly divided into ALPPS group, portal vein ligation group (PVL group), and sham operation group (Sham group), 24 mice in each group. And then one-stage ALPPS operation, simple PVL, and sham operation will be performed. Six mice were randomized selected of the three groups on the 1^st, 2^nd, 4^th, and 7^th day after surgery, respectively, the liver weight to body weight ratio (FLR/BW) of each group was measured, and the liver tissues were taken for immunohistochemical staining to calculate the proportion of Ki-67 positive cells, Western blot was used to detect the expression levels of X-box binding protein 1 (XBP1) and inositol-requiring enzyme 1α (IRE1α) proteins.Results ① FLR/BW: On the 4^th day and the 7^th day after operation, the FLR/BW of the Sham group, PVL group, and ALPPS group increased in sequence at the same time, and the difference between the three groups was statistically significant (P<0.05). ② Ki-67 positive cell ratio: On the 2^nd day after operation, the ratio of Ki-67 positive cells in the Sham group, PVL group, and ALPPS group increased sequentially, and the difference between the two groups was statistically significant (P<0.05). On the 4^th day after operation, the ratio of Ki-67 positive cells in the PVL group and the ALPPS group were still higher than that of the Sham group (P<0.05). ③ Expression levels of XBP1 and IRE1α: On the 2^nd and 4^th postoperative day, the expression levels of XBP1 and IRE1α in the ALPPS group were higher than those in the Sham group and the PVL group (P<0.05). On the 7^th day after surgery, the expression levels of XBP1 and IRE1α in the ALPPS group were higher than those in the Sham group (P<0.05), while compared with the PVL group, the expression level of XBP1 in the ALPPS group was still higher (P<0.05).Conclusions ALPPS-induced liver regeneration is more advantageous than traditional PVL in mice. It may be attributed to the obvious endoplasmic reticulum stress activation after ALPPS leading to the up-regulation of IRE1α-XBP1 expression, which is involved in the regulation of hepatocyte cell cycle and promotes hepatocyte proliferation, thus promoting rapid liver regeneration.

Citation： GONG Qi, XU Feng, ZHAO Liang, DAI Chaoliu. Relationship between liver regeneration after ALPPS and endoplasmic reticulum stress IRE1α-XBP1 pathway. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(10): 1162-1169. doi: 10.7507/1007-9424.201905046 Copy

1.	Sun JY, Yin T, Zhang XY, et al. Therapeutic advances for patients with intermediate hepatocellular carcinoma. J Cell Physiol, 2019, 234(8): 12116-12121.
2.	Agrawal S, Belghiti J. Oncologic resection for malignant tumors of the liver. Ann Surg, 2011, 253(4): 656-665.
3.	Robles R, Parrilla P, López-Conesa A, et al. Tourniquet modification of the associating liver partition and portal ligation for staged hepatectomy procedure. Br J Surg, 2014, 101(9): 1129-1134.
4.	Kikuchi Y, Hiroshima Y, Matsuo K, et al. Impact of associating liver partition and portal vein occlusion for staged hepatectomy on tumor growth in a mouse model of liver metastasis. Eur J Surg Oncol, 2018, 44(1): 130-138.
5.	Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg, 2012, 255(3): 405-414.
6.	Cai YL, Song PP, Tang W, et al. An updated systematic review of the evolution of ALPPS and evaluation of its advantages and disadvantages in accordance with current evidence. Medicine (Baltimore), 2016, 95(24): e3941.
7.	Zhao J, Xu H, Li Y, et al. NAFLD induction delays postoperative liver regeneration of ALPPS in rats. Dig Dis Sci, 2019, 64(2): 456-468.
8.	Tarlow BD, Pelz C, Naugler WE, et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell, 2014, 15(5): 605-618.
9.	Parker R, Phan T, Baumeister P, et al. Identification of TFII-I as the endoplasmic reticulum stress response element binding factor ERSF: its autoregulation by stress and interaction with ATF6. Mol Cell Biol, 2001, 21(9): 3220-3233.
10.	Kratochvílová K, Moráň L, Paďourová S, et al. The role of the endoplasmic reticulum stress in stemness, pluripotency and development. Eur J Cell Biol, 2016, 95(3-5): 115-123.
11.	Xu H, Tsang KS, Wang Y, et al. Unfolded protein response is required for the definitive endodermal specification of mouse embryonic stem cells via Smad2 and β-catenin signaling. J Biol Chem, 2014, 289(38): 26290-26301.
12.	Guo FJ, Jiang R, Xiong Z, et al. Expression of concern to IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiation. Cell Death Dis, 2018, 9(11): 1124.
13.	Kawada K, Iekumo T, Saito R, et al. Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress. J Neurosci Res, 2014, 92(9): 1122-1133.
14.	Bickler PE, Clark JP, Gabatto P, et al. Hypoxic preconditioning and cell death from oxygen/glucose deprivation co-opt a subset of the unfolded protein response in hippocampal neurons. Neuroscience, 2015, 310: 306-321.
15.	Chen L, Liu L, Xie ZY, et al. Endoplasmic reticulum stress facilitates the survival and proliferation of nucleus pulposus cells in TNF-α stimulus by activating unfolded protein response. DNA Cell Biol, 2018, 37(4): 347-358.
16.	Fujimoto A, Kawana K, Taguchi A, et al. Inhibition of endoplasmic reticulum (ER) stress sensors sensitizes cancer stem-like cells to ER stress-mediated apoptosis. Oncotarget, 2016, 7(32): 51854-51864.
17.	Blazanin N, Son J, Craig-Lucas AB, et al. ER stress and distinct outputs of the IRE1α RNase control proliferation and senescence in response to oncogenic Ras. Proc Natl Acad Sci U S A, 2017, 114(37): 9900-9905.
18.	Schlegel A, Lesurtel M, Melloul E, et al. ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration. Ann Surg, 2014, 260(5): 839-847.
19.	Golriz M, Majlesara A, El Sakka S, et al. Small for Size and Flow (SFSF) syndrome: an alternative description for posthepatectomy liver failure. Clin Res Hepatol Gastroenterol, 2016, 40(3): 267-275.
20.	Schadde E, Ardiles V, Slankamenac K, et al. ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors compared with conventional-staged hepatectomies: results of a multicenter analysis. World J Surg, 2014, 38(6): 1510-1519.
21.	Aghayeva A, Baca B, Atasoy D, et al. Portal vein ligation and in situ liver splitting in metastatic liver cancer. Turk J Surg, 2018, 34(4): 327-330.
22.	Maggiori L, Bretagnol F, Sibert A, et al. Selective portal vein ligation and embolization induce different tumoral responses in the rat liver. Surgery, 2011, 149(4): 496-503.
23.	Vennarecci G, Ferraro D, Tudisco A, et al. The ALPPS procedure: hepatocellular carcinoma as a main indication. An Italian single-center experience. Updates Surg, 2019, 71(1): 67-75.
24.	Huiskens J, Schadde E, Lang H, et al. Avoiding postoperative mortality after ALPPS-development of a tumor-specific risk score for colorectal liver metastases. HPB (Oxford), 2019, 21(7): 898-905.
25.	Mao SA, Glorioso JM, Nyberg SL. Liver regeneration. Transl Res, 2014, 163(4): 352-362.
26.	Kim AR, Park JI, Oh HT, et al. TAZ stimulates liver regeneration through interleukin-6-induced hepatocyte proliferation and inhibition of cell death after liver injury. FASEB J, 2019, 33(5): 5914-5923.
27.	Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: from physiopathology to therapy. J Hepatol, 2016, 64(6): 1403-1415.
28.	Liu Y, Yang F, Li J, et al. Mesenchymal stem cells enhance liver regeneration via improving lipid accumulation and hippo signaling. Stem Cells Int, 2018, 2018: 7652359.
29.	Tao Y, Wang M, Chen E, et al. Liver regeneration: analysis of the main relevant signaling molecules. Mediators Inflamm, 2017, 2017: 4256352.
30.	Tanaka K, Matsuo K, Murakami T, et al. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): short-term outcome, functional changes in the future liver remnant, and tumor growth activity. Eur J Surg Oncol, 2015, 41(4): 506-512.
31.	Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science, 2011, 334(6059): 1081-1086.
32.	Xu T, Yang L, Yan C, et al. The IRE1α-XBP1 pathway regulates metabolic stress-induced compensatory proliferation of pancreatic β-cells. Cell Res, 2014, 24(9): 1137-1140.
33.	Liu Y, Shao M, Wu Y, et al. Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses. J Hepatol, 2015, 62(3): 590-598.
34.	Qiu Q, Zheng Z, Chang L, et al. Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis. EMBO J, 2013, 32(18): 2477-2490.
35.	Argemí J, Kress TR, Chang HCY, et al. X-box binding protein 1 regulates unfolded protein, acute-phase, and dna damage responses during regeneration of mouse liver. Gastroenterology, 2017, 152(5): 1203-1216.e15.

1. Sun JY, Yin T, Zhang XY, et al. Therapeutic advances for patients with intermediate hepatocellular carcinoma. J Cell Physiol, 2019, 234(8): 12116-12121.
2. Agrawal S, Belghiti J. Oncologic resection for malignant tumors of the liver. Ann Surg, 2011, 253(4): 656-665.
3. Robles R, Parrilla P, López-Conesa A, et al. Tourniquet modification of the associating liver partition and portal ligation for staged hepatectomy procedure. Br J Surg, 2014, 101(9): 1129-1134.
4. Kikuchi Y, Hiroshima Y, Matsuo K, et al. Impact of associating liver partition and portal vein occlusion for staged hepatectomy on tumor growth in a mouse model of liver metastasis. Eur J Surg Oncol, 2018, 44(1): 130-138.
5. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg, 2012, 255(3): 405-414.
6. Cai YL, Song PP, Tang W, et al. An updated systematic review of the evolution of ALPPS and evaluation of its advantages and disadvantages in accordance with current evidence. Medicine (Baltimore), 2016, 95(24): e3941.
7. Zhao J, Xu H, Li Y, et al. NAFLD induction delays postoperative liver regeneration of ALPPS in rats. Dig Dis Sci, 2019, 64(2): 456-468.
8. Tarlow BD, Pelz C, Naugler WE, et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell, 2014, 15(5): 605-618.
9. Parker R, Phan T, Baumeister P, et al. Identification of TFII-I as the endoplasmic reticulum stress response element binding factor ERSF: its autoregulation by stress and interaction with ATF6. Mol Cell Biol, 2001, 21(9): 3220-3233.
10. Kratochvílová K, Moráň L, Paďourová S, et al. The role of the endoplasmic reticulum stress in stemness, pluripotency and development. Eur J Cell Biol, 2016, 95(3-5): 115-123.
11. Xu H, Tsang KS, Wang Y, et al. Unfolded protein response is required for the definitive endodermal specification of mouse embryonic stem cells via Smad2 and β-catenin signaling. J Biol Chem, 2014, 289(38): 26290-26301.
12. Guo FJ, Jiang R, Xiong Z, et al. Expression of concern to IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiation. Cell Death Dis, 2018, 9(11): 1124.
13. Kawada K, Iekumo T, Saito R, et al. Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress. J Neurosci Res, 2014, 92(9): 1122-1133.
14. Bickler PE, Clark JP, Gabatto P, et al. Hypoxic preconditioning and cell death from oxygen/glucose deprivation co-opt a subset of the unfolded protein response in hippocampal neurons. Neuroscience, 2015, 310: 306-321.
15. Chen L, Liu L, Xie ZY, et al. Endoplasmic reticulum stress facilitates the survival and proliferation of nucleus pulposus cells in TNF-α stimulus by activating unfolded protein response. DNA Cell Biol, 2018, 37(4): 347-358.
16. Fujimoto A, Kawana K, Taguchi A, et al. Inhibition of endoplasmic reticulum (ER) stress sensors sensitizes cancer stem-like cells to ER stress-mediated apoptosis. Oncotarget, 2016, 7(32): 51854-51864.
17. Blazanin N, Son J, Craig-Lucas AB, et al. ER stress and distinct outputs of the IRE1α RNase control proliferation and senescence in response to oncogenic Ras. Proc Natl Acad Sci U S A, 2017, 114(37): 9900-9905.
18. Schlegel A, Lesurtel M, Melloul E, et al. ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration. Ann Surg, 2014, 260(5): 839-847.
19. Golriz M, Majlesara A, El Sakka S, et al. Small for Size and Flow (SFSF) syndrome: an alternative description for posthepatectomy liver failure. Clin Res Hepatol Gastroenterol, 2016, 40(3): 267-275.
20. Schadde E, Ardiles V, Slankamenac K, et al. ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors compared with conventional-staged hepatectomies: results of a multicenter analysis. World J Surg, 2014, 38(6): 1510-1519.
21. Aghayeva A, Baca B, Atasoy D, et al. Portal vein ligation and in situ liver splitting in metastatic liver cancer. Turk J Surg, 2018, 34(4): 327-330.
22. Maggiori L, Bretagnol F, Sibert A, et al. Selective portal vein ligation and embolization induce different tumoral responses in the rat liver. Surgery, 2011, 149(4): 496-503.
23. Vennarecci G, Ferraro D, Tudisco A, et al. The ALPPS procedure: hepatocellular carcinoma as a main indication. An Italian single-center experience. Updates Surg, 2019, 71(1): 67-75.
24. Huiskens J, Schadde E, Lang H, et al. Avoiding postoperative mortality after ALPPS-development of a tumor-specific risk score for colorectal liver metastases. HPB (Oxford), 2019, 21(7): 898-905.
25. Mao SA, Glorioso JM, Nyberg SL. Liver regeneration. Transl Res, 2014, 163(4): 352-362.
26. Kim AR, Park JI, Oh HT, et al. TAZ stimulates liver regeneration through interleukin-6-induced hepatocyte proliferation and inhibition of cell death after liver injury. FASEB J, 2019, 33(5): 5914-5923.
27. Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: from physiopathology to therapy. J Hepatol, 2016, 64(6): 1403-1415.
28. Liu Y, Yang F, Li J, et al. Mesenchymal stem cells enhance liver regeneration via improving lipid accumulation and hippo signaling. Stem Cells Int, 2018, 2018: 7652359.
29. Tao Y, Wang M, Chen E, et al. Liver regeneration: analysis of the main relevant signaling molecules. Mediators Inflamm, 2017, 2017: 4256352.
30. Tanaka K, Matsuo K, Murakami T, et al. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): short-term outcome, functional changes in the future liver remnant, and tumor growth activity. Eur J Surg Oncol, 2015, 41(4): 506-512.
31. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science, 2011, 334(6059): 1081-1086.
32. Xu T, Yang L, Yan C, et al. The IRE1α-XBP1 pathway regulates metabolic stress-induced compensatory proliferation of pancreatic β-cells. Cell Res, 2014, 24(9): 1137-1140.
33. Liu Y, Shao M, Wu Y, et al. Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses. J Hepatol, 2015, 62(3): 590-598.
34. Qiu Q, Zheng Z, Chang L, et al. Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis. EMBO J, 2013, 32(18): 2477-2490.
35. Argemí J, Kress TR, Chang HCY, et al. X-box binding protein 1 regulates unfolded protein, acute-phase, and dna damage responses during regeneration of mouse liver. Gastroenterology, 2017, 152(5): 1203-1216.e15.

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Relationship between liver regeneration after ALPPS and endoplasmic reticulum stress IRE1α-XBP1 pathway

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