Autophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression.

In our published work, we reported that HMGB1 is actively released from autophagy-deficient hepatocytes via a pathway from NRF2 to inflammasomes to promote ductular reaction, hepatic progenitor cell expansion, and tumorigenesis. We based our conclusions on multiple lines of evidence. Release of HMGB1 from autophagy-deficient hepatocytes was documented by immunoblotting, immunostaining, and ELISA analysis in different age groups of autophagy-deficient mice. The release of HMGB1 through an active mechanism is supported by kinetics analysis that shows tissue injury can be separated from the release process and by pharmacological and genetic analyses showing that the molecular elements of NRF2 and CASPASE 1 are required. The impact of HMGB1 on ductular reaction and tumor progression was also documented by both in vivo and in vitro evidence using knockout mice, cell fractionation, and transcriptional analysis. Figure 1G showed the results of an analysis of HMGB1 isoforms by mass spectrometry that was undertaken in a separate laboratory by Daniel J. Antoine. In February 2019, we learned that these data were likely compromised. We contacted the journal, and the Editorial Board gave us permission to correct the study. In the corrected version, all conclusions based on Figure 1G have been removed, and the journal has published an online version of the original article with the unreliable statements crossed out and the modified text highlighted in red (Supplemental File, Redaction). Figure 1G only suggested the formation of the released HMGB1, but carried no significance as to the releasing mechanisms and the functional significance of HMGB1 release in autophagy-deficient conditions. We thus believe that the major conclusions of the study on the releasing mechanism and functional significance of HMGB1 in autophagy-deficient conditions are independent of Figure 1G and are accurate and that the corrected paper is reliable.

Several lines of evidence suggest that defects in telomere maintenance play a significant role in the initiation of genomic instability during carcinogenesis. Although the general concept of defective telomere maintenance initiating genomic instability has been acknowledged, there remains a critical gap in the direct evidence of telomere dysfunction in human solid tumors. To address this topic, we devised a multiplex PCR-based assay, termed TAR (telomereassociated repeat) fusion PCR, to detect and analyze chromosome end-to-end associations (telomere fusions) within human breast tumor tissue. Using TAR fusion PCR, we found that human breast lesions, but not normal breast tissues from healthy volunteers, contained telomere fusions. Telomere fusions were detected at similar frequencies during early ductal carcinoma in situ and in the later invasive ductal carcinoma stage. Our results provide direct evidence that telomere fusions are present in human breast tumor tissue and suggest that telomere dysfunction may be an important component of the genomic instability observed in this cancer. Development of this robust method that allows identification of these genetic aberrations (telomere fusions) is anticipated to be a valuable tool for dissecting mechanisms of telomere dysfunction.breast cancer | retrotransposon D efects in telomere maintenance have been suggested to play significant roles in the initiation of genomic instability via breakage-fusion-bridge cycles and aneuploidy, which are associated with the development of human cancers, including breast cancer (1, 2). A critical function of the telomere is to disguise the chromosome end from being recognized as a double-strand break, to prevent aberrant chromosomal end joining and recombination events. Cells disguise telomeric DNA by encapsulating or "capping" the chromosome ends with several telomere-associated proteins and unique telomere-specific structures (3). In healthy cells, telomere length is highly regulated in a tissue-and cell typespecific manner and is dependent on mitotic turnover rate, telomerase activity, and telomerase-associated factors (4, 5).Several lines of evidence from mouse and human systems suggest that defects in telomere maintenance play an important role in the development of cancer (1, 2). Induction of telomere dysfunction by deficiency in the telomerase RNA component (mTER) in a p53 mutant mouse background results in significant levels of breast adenocarcinomas and colon carcinomas (6-8). Telomere dysfunction also has been reported in a human mammary epithelial cell culture model (9). In this model, late-passage human mammary epithelial cell escape a stress-associated senescencelike barrier and acquire genomic alterations, including telomere fusions (9). In addition, clinical studies have shown that a significant proportion of normal breast luminal cells and ductal carcinoma in situ (DCIS) tissues have shortened telomeric DNA lengths when assayed by telomere FISH (10). Several studies have reported that anaphase bridges, possibly formed...

Telomeres are essential for genomic integrity, but little is known about their regulation in the normal human mammary gland. We now demonstrate that a phenotypically defined cell population enriched in luminal progenitors (LPs) is characterized by unusually short telomeres independently of donor age. Furthermore, we find that multiple DNA damage response proteins colocalize with telomeres in >95% of LPs but in <5% of basal cells. Paradoxically, 25% of LPs are still capable of exhibiting robust clonogenic activity in vitro. This may be partially explained by the elevated telomerase activity that was also seen only in LPs. Interestingly, this potential telomere salvage mechanism declines with age. Our findings thus reveal marked differences in the telomere biology of different subsets of primitive normal human mammary cells. The chronically dysfunctional telomeres unique to LPs have potentially important implications for normal mammary tissue homeostasis as well as the development of certain breast cancers.

Autophagy is an evolutionarily conserved intracellular degradative function that is important for liver homeostasis. Accumulating evidence suggests that autophagy is deregulated during the progression and development of alcoholic and non-alcoholic liver diseases. Impaired autophagy prevents the clearance of excessive lipid droplets (LDs), damaged mitochondria, and toxic protein aggregates, which can be generated during the progression of various liver diseases, thus contributing to the development of steatosis, injury, steatohepatitis, fibrosis, and tumors. In this review, we look at the status of hepatic autophagy during the pathogenesis of alcoholic and non-alcoholic liver diseases. We also examine the mechanisms of defects in autophagy, and the hepato-protective roles of autophagy in non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), focusing mainly on steatosis and liver injury. Finally, we discuss the therapeutic potential of autophagy modulating agents for the treatment of these two common liver diseases.