The role of interleukin-8 in pancreatic cancer cachexia

  • 陳 浩雲

Student thesis: Master's Thesis

Abstract

Pancreatic cancer is the fourth most common cause of cancer-related death in the Western countries and has a poor prognosis In Taiwan pancreatic cancer is responsible for about 4% of all cancer deaths The most common type accounting for 95% of these tumors is adenocarcinoma Pancreatic cancers can metastasize very early in their development and are diagnosed in advanced stages It is estimated that more than 80% of patients with pancreatic cancer experience cancer-induced cachexia the main cause of death in approximately 20% of cancer patients The major characteristic of cachexia is skeletal muscle atrophy that leads to body weight loss In addition inflammation anorexia insulin resistance weakness fatigue loss of fat mass and abnormal biochemistry also frequently occur in the cachexia patients Interleukin-8 (IL-8) a pro-inflammatory cytokine has been reported to be associated with both weakness and lack of appetite; however its role on pancreatic cancer-induced cachexia remains to be explored In this study we statistically analyzed the correlation between IL-8 expression and pancreatic cancer cachexia using clinical samples Furthermore we established a syngeneic orthotopic pancreatic cancer cachexia model in C57B/L6 mice using primary mouse cancer cells line from KrasG12D; Trp53R172H; Pdx1-Cre (KPC) mice to investigate whether IL-8 can induce cancer cachexia in vivo We also used mouse myoblasts C2C12 to study the mechanism underlying the induction of cachexia by IL-8 We found that IL-8 levels were significantly increased in serum of patients with pancreatic cancer High IL-8 levels in the tumor tissues or serum were associated with body weight loss and poor patient outcomes Moreover we observed muscle wasting in hindlimb muscles and significant body weight loss in the cachexia mouse model In in vitro experiments we found that IL-8 could up-regulate ubiquitin ligase (MuRF1) by activating NF-κB signaling in C2C12 cells Taken together these results suggest that IL-8 is involved in cachexia induction in pancreatic cancer patients IL-8 may activate the ubiquitin proteasome system via NF-κB in muscular cells Targeting IL-8 may be a promising therapy for pancreatic cancer patients especially for those with cachexia
Date of Award2015 Sep 3
Original languageEnglish
SupervisorYan-Shen Shan (Supervisor)

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