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Chaperone-mediated autophagy compensates for impaired macroautophagy in the cirrhotic liver to promote hepatocellular carcinoma.

ABSTRACT: Macroautophagy and chaperone-mediated autophagy (CMA) represent two major lysosomal degradation processes and often compensate for one another to facilitate cell survival. The aim of this study was to determine whether these autophagy pathways could compensate for one another to promote HCC cell survival in the cirrhotic liver. Analysis of normal liver tissue showed no expression of glypican-3 or p62 proteins, suggesting that macroautophagy is the major contributor to autophagic flux under non-pathological conditions. Of 46 cirrhotic livers with HCC examined, 39 (84%) of HCCs showed increased expression of p62, and 36 (78%) showed increased expression of glypican-3, while adjacent non-tumorous hepatocytes were negative for expression of p62 and glypican-3, similar to normal liver tissue. These results suggest that macroautophagy flux is impaired in HCC. Furthermore, more than 95% of HCCs showed altered expression of LAMP-2A compared to the surrounding non-tumorous cirrhotic liver, consistent with induction of CMA in HCC. Elevated expression of glucose-regulated protein 78 (GRP78) and heat shock cognate protein (Hsc70) were detected in 100% of HCC and adjacent non-tumorous cirrhotic livers, suggesting that unresolved ER-stress is associated with HCC risk in liver cirrhosis. Interestingly, inhibition of lysosomal degradation using hydroxychloroquine (HCQ) induced expression of the tumor suppressor p53, promoted apoptosis, and inhibited HCC growth, whereas activation of autophagy using an mTOR inhibitor (Torin1) promoted HCC growth. Results of this study suggest that induction of CMA compensates for the impairment of macroautophagy to promote HCC survival in the cirrhotic liver.

SUBMITTER: Chava S

PROVIDER: S-EPMC5522234 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Chaperone-mediated autophagy compensates for impaired macroautophagy in the cirrhotic liver to promote hepatocellular carcinoma.

Chava Srinivas S Lee Christine C Aydin Yucel Y Chandra Partha K PK Dash Asha A Chedid Milad M Thung Swan N SN Moroz Krzysztof K Wu Tong T Nayak Nabeen C NC Dash Srikanta S

Oncotarget 20170601 25

Macroautophagy and chaperone-mediated autophagy (CMA) represent two major lysosomal degradation processes and often compensate for one another to facilitate cell survival. The aim of this study was to determine whether these autophagy pathways could compensate for one another to promote HCC cell survival in the cirrhotic liver. Analysis of normal liver tissue showed no expression of glypican-3 or p62 proteins, suggesting that macroautophagy is the major contributor to autophagic flux under non-p ...[more]

PMID: 28402954

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Project description:BACKGROUND: The laparoscopic approach for liver resections is still limited and controversial. Nevertheless the advantages connected with a mini-invasive approach are significant, especially in cirrhotic patients. In recent years the progress of laparoscopic procedures and the development of new and dedicated technologies have made endoscopic hepatic surgery feasible and safe. The aim of this study was to report the results of our experience in laparoscopic liver surgery for hepatocellular carcinoma (HCC) in cirrhotic patients. METHODS: From 2000 to 2003, 16 patients (10 male, 6 female; age 48-69 years; mean age 60.1 years) with HCC and associated severe but well compensated liver cirrhosis underwent laparoscopic hepatic resections at our department. Mean tumour size was 2.9 cm (range 1-3.9). Seven of these lesions were in the left liver and nine in the right lobe. Laparoscopy was performed under CO(2) pneumoperitoneum. The liver was always examined using laparoscopic ultrasound (US) to confirm the extension of the lesions and their relationships to the vasculature. The Pringle manoeuvre was not used. The transection of liver parenchyma was obtained by the use of a harmonic scalpel. The specimens were placed in a plastic bag and removed without contact to the abdominal wall. RESULTS: There was one conversion to laparotomy for inadequate exposure. In the remaining 15 patients we performed 13 non-anatomical resections, I segmentectomy and I anatomical left lobectomy. The mean operative time was 152 min (range 80-180). Mean blood loss was 280 ml and none of the patients required blood transfusions. In two patients the resection margin was <1 cm but the capsule was not infiltrated at histology. One patient died on the third postoperative day from a severe respiratory distress syndrome. Major morbidities occurred in two patients who developed moderate postoperative ascites, which resolved successfully with conservative treatment. The mean postoperative hospital stay was 8.8 days. Mean follow-up time has been 18 months, and to date no recurrences at the site of resection or port-site metastases have been observed. DISCUSSION: Limited laparoscopic liver resections in cirrhotic patients are technically feasible with a low complication rate when careful selection criteria are followed (hepatic involvement limited and located in the left or anterior right segments, tumour size smaller than 5 cm, Child-Pugh class A). This approach could be considered the best option for the treatment of small esophitic or subcapsular HCC on well compensated cirrhosis and a useful option when it is necessary to perform a left lateral anatomical resection or non-anatomical resection in well selected patients. In fact the mini-invasive approach can minimise the postoperative morbidity rate, which is still too high in this group of patients. It must be performed in highly specialised units by surgeons assisted by all requested technologies and with extensive experience in hepatobiliary and advanced laparoscopic surgery.

Project description:BackgroundLimited anatomical liver resection for hepatocellular carcinoma (HCC) is complicated in cirrhotic patients with centrally located HCC and limited liver reserve. We present a case of total laparoscopic left medial and right ventroanterior sectionectomy performed using the intrahepatic Glissonian approach in a cirrhotic liver for curative resection of HCC.MethodsThe patient was a 69-year-old man with a 6.5-cm-diameter HCC located at segments 4, 5, and 8 and which was compressing the middle hepatic vein (MHV). Child-Pugh class A liver cirrhosis was noted, and the 15-min retention rate for indocyanine green was 14 %. Preoperative surgical planning suggested the feasibility of limited anatomical subsegmental resection. The patient was placed in the supine position and 5 trocars were used for the procedure. The operation began with cholecystectomy, division of liver ligaments, and exposure of the right hepatic vein root and the umbilical Glissonian pedicles to the left medial segment. Parenchymal transection was performed using a laparoscopic harmonic scalpel and Cavitron Ultrasonic Surgical Aspirator until the MHV was reached. After exposing the ventral branches of the right anterior Glissonian pedicle and dividing them, resection was continued along the demarcation line. Fissure veins draining to the MHV root were identified and divided. The MHV root was closed using an automatic stapler.ResultsThe operation time was 565 min and estimated blood loss was 665 ml; blood transfusion was not required. Pathological examination confirmed a moderately differentiated HCC with all resected margins free of malignancy. Postoperative recovery was uneventful and the patient was discharged on the postoperative day 7. There was no tumor recurrence 18 months after the operation.ConclusionsTotal laparoscopic left medial and right ventroanterior sectionectomy via the intrahepatic Glissonian approach is feasible for HCC in a cirrhotic liver with limited liver reserve. Preoperative planning is essential in order to compute successful hepatic function. Standardization of surgical techniques may aid in safely performing this procedure.

Dataset Information

Chaperone-mediated autophagy compensates for impaired macroautophagy in the cirrhotic liver to promote hepatocellular carcinoma.

Publications

Chaperone-mediated autophagy compensates for impaired macroautophagy in the cirrhotic liver to promote hepatocellular carcinoma.

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