Cancer-associated fibroblast spatial heterogeneity and EMILIN1 expression in the tumor microenvironment modulate TGF-ß activity and CD8+ T-cell infiltration in breast cancer.

Rationale: The tumor microenvironment (TME) and its multifaceted interactions with cancer cells are major targets for cancer treatment. Single-cell technologies have brought major insights into the TME, but the resulting complexity often precludes conclusions on function. Methods: We combined single-cell RNA sequencing and spatial transcriptomic data to explore the relationship between different cancer-associated fibroblast (CAF) populations and immune cell exclusion in breast tumors. The significance of the findings was then evaluated in a cohort of tumors (N=75) from breast cancer patients using immunohistochemistry analysis. Results: Our data show for the first time the degree of spatial organization of different CAF populations in breast cancer. We found that IL-iCAFs, Detox-iCAFs, and IFNγ-iCAFs tended to cluster together, while Wound-myCAFs, TGFß-myCAFs, and ECM-myCAFs formed another group that overlapped with elevated TGF-ß signaling. Differential gene expression analysis of areas with CD8+ T-cell infiltration/exclusion within the TGF-ß signaling-rich zones identified elastin microfibrillar interface protein 1 (EMILIN1) as a top modulated gene. EMILIN1, a TGF-ß inhibitor, was upregulated in IFNγ-iCAFs directly modulating TGFß immunosuppressive function. Histological analysis of 75 breast cancer samples confirmed that high EMILIN1 expression in the tumor margins was related to high CD8+ T-cell infiltration, consistent with our spatial gene expression analysis. High EMILIN1 expression was also associated with better prognosis of patients with breast cancer, underscoring its functional significance for the recruitment of cytotoxic T cells into the tumor area. Conclusion: Our data show that correlating TGF-ß signaling to a CAF subpopulation is not enough because proteins with TGF-ß-modulating activity originating from other CAF subpopulations can alter its activity. Therefore, therapeutic targeting should remain focused on biological processes rather than on specific CAF subtypes.

Effectiveness of Combination Chemotherapy With Docetaxel, Nedaplatin, and 5-Fluorouracil for Advanced and Recurrent Esophageal Cancer.

BACKGROUND/AIM: Chemotherapy and immunotherapy have been recently developed as potentially useful first-line treatments for unresectable, advanced, or recurrent esophageal cancer. We performed a retrospective study of the therapeutic effectiveness of triplet chemotherapy with docetaxel, nedaplatin, and 5-fluorouracil therapy for advanced, recurrent, and unresectable advanced esophageal cancer at our hospital and compared the regimen's results with those of current and possible future treatment options. PATIENTS AND METHODS: The study cohort comprised 101 patients who received docetaxel, nedaplatin, and 5-fluorouracil for advanced or recurrent esophageal cancer at Gunma University from May 2008 to December 2017. We retrospectively evaluated the results of this combination chemotherapy and postulated future treatment strategies. RESULTS: The overall response and disease control rates, the latter including stable disease, for docetaxel, nedaplatin, and 5-fluorouracil were 33.6% and 61.4%, respectively. The median overall survival and progression-free survival were 12.26 months and 5.1 months, respectively. In patients with recurrence, the median overall and progression-free survivals were 14.97 months (449 days) and 5.1 months (152 days), respectively. No study patients developed acute kidney injury and there were no treatment-related deaths. However, leukopenia and neutropenia were frequent hematologic toxicities. CONCLUSION: Treatment with docetaxel, nedaplatin, and 5-fluorouracil for advanced or recurrent esophageal cancer is particularly useful for recurrent cases and has the advantage of not causing severe renal dysfunction.

Prognostic value of a modified­immune scoring system in patients with pathological T4 colorectal cancer.

Tumor-infiltrating immune cells, such as lymphocytes and macrophages, have been associated with tumor aggressiveness, prognosis and treatment response in colorectal cancer (CRC). An immune scoring system, Immunoscore (IS), based on tumor-infiltrating T cells in stage I-III CRC, was used to predict prognosis. An alternative immune scoring signature of immune activation (SIA) reflects the balance between anti- and pro-tumoral immune components. The present study aimed to evaluate the prognostic value of modified IS (mIS) and modified SIA (mSIA) in locally advanced pathological T4 (pT4) CRC, including stage IV CRC. Immunohistochemical staining for immune cell markers, such as CD3 (pan-T cell marker), CD8 (anti-tumoral cytotoxic T cell marker) and CD163 (tumor-supportive macrophage marker), in specimens from patients with radically resected pT4 CRC at stages II-IV was performed. mIS levels in the T4 CRC cohort were not associated with prognosis. However, low mSIA levels were associated with low survival. Furthermore, low mSIA was an independent predictor of recurrence in patients with radically resected pT4 CRC. In patients with CRC who did not receive postoperative adjuvant chemotherapy, low mSIA was a major poor prognostic factor; however, this was not observed in patients receiving adjuvant chemotherapy. Evaluation of the tumor-infiltrating immune cell population could serve as a valuable marker of recurrence and poor prognosis in patients with locally advanced CRC. mSIA assessment after radical CRC resection may be promising for identifying high-risk patients with pT4 CRC who require aggressive adjuvant chemotherapy.

Potential of Mac-2-binding protein glycan isomer as a new therapeutic target in pancreatic cancer.

Pancreatic cancer (PC) is a challenging malignancy to treat. Mac-2-binding protein glycan isomer (M2BPGi) is a novel serum marker of liver fibrosis and hepatocellular carcinoma and is secreted by hepatic stellate and stroma cells. Serum M2BPGi levels are upregulated in PC patients. We measured the expression of M2BPGi in the serum of 27 PC patients and determined whether M2BPGi affects the malignant potential of PC cells in vitro. We also examined the effect of M2BP on PC tumor growth and gemcitabine sensitivity in vivo. Serum M2BPGi levels in PC patients were higher compared with those of healthy subjects. M2BPGi extraction in cancer-associated fibroblasts (CAFs) was higher compared with that of PC cells. M2BPGi treatment promoted the proliferation and invasion of PC cells. The suppression of galectin-3, which binds to M2BPGi, did not affect the proliferation-promoting effect of M2BPGi in PC cells. The suppression of M2BP reduced tumor growth and enhanced gemcitabine sensitivity in PC-bearing xenograft mice. CAF-derived M2BPGi promotes the proliferation and invasion of PC cells. Targeting M2BPGi may represent a new therapeutic strategy to circumvent refractory PC.

Efficacy of thoracic endovascular aortic repair for aorto-esophageal fistula due to esophageal cancer: a systematic review and meta-analysis.

Aorto-esophageal fistula (AEF) due to esophageal cancer (EC) is a life-threatening condition characterized by sudden hemorrhage, which often causes sudden death. To evaluate the efficacy and safety of thoracic endovascular aortic repair (TEVAR) for AEF due to EC, we performed a systematic review and meta-analysis. We searched the MEDLINE (PubMed) databases, the Cochrane Library databases, Ichushi-Web (the databases of the Japan Medical Abstract Society), and CiNii (Academic information search service of the National Institute of Information from Japan) from January 2000 to November 2023 for articles about TEVAR for an emergent aortic hemorrhage (salvage TEVAR [S-TEVAR]), and the prophylactic procedure (P-TEVAR). Six studies (140 cases) were eligible for meta-analysis. The 90-day mortality of S-TEVAR and P-TEVAR was 40% (95% CI 23-60, I2 = 36%) and 8% (95% CI 3-17, I2 = 0%), respectively. Post-S-TEVAR hemorrhagic and infectious complications were 17% (95% CI 3-57, I2 = 71%) and 20% (95% CI 5-57, I2 = 66%), respectively. Post-P-TEVAR hemorrhagic and infectious complications were 2% (95% CI 0-10, I2 = 0%) and 3% (95% CI 1-12, I2 = 0%), respectively. TEVAR for AEF due to EC may be a useful therapeutic option to manage or prevent hemorrhagic oncological emergencies.

RNF31 promotes proliferation and invasion of hepatocellular carcinoma via nuclear factor kappaB activation.

RNF31 is a multifunctional RING finger protein implicated in various inflammatory diseases and cancers. It functions as a core component of the linear ubiquitin chain assembly complex (LUBAC), which activates the nuclear factor kappaB (NF-κB) pathway via the generation of the Met1-linked linear ubiquitin chain. We aimed to clarify the role of RNF31 in the pathogenesis of hepatocellular carcinoma (HCC) and its relevance as a therapeutic target. High RNF31 expression in HCC, assessed by both immunohistochemistry and mRNA levels, was related to worse survival rates among patients with HCC. In vitro experiments showed that RNF31 knockdown in HCC cell lines led to decreased cell proliferation and invasion, as well as suppression of tumor necrosis factor (TNF)-α-induced NF-κB activation. Treatment with HOIPIN-8, a specific LUBAC inhibitor that suppresses RNF31 ubiquitin ligase (E3) activity, showed similar effects, resulting in decreased cell proliferation and invasion. Our clinical and in vitro data showed that RNF31 is a prognostic factor for HCC that promotes tumor aggressiveness via NF-κB activation.

Liver regeneration after hepatectomy is significantly suppressed in a muscular atrophy mouse model.

BACKGROUND: Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength. As reported in previous studies, the loss of skeletal muscle mass is associated with poor liver regeneration after hepatectomy. It is considered important to clarify the effect of sarcopenia on liver regeneration; however, there are no reports about model animals for sarcopenia. We focused on the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) transgenic mice that overexpressed PGC-1α, specifically for skeletal muscle, and showed significant atrophy of type 2B fiber-rich muscles like sarcopenia. METHODS: We performed 70% hepatectomy using PGC-1α transgenic mice and examined the liver regeneration rate and the effects of branched-chain amino acids (BCAA) after hepatectomy. RESULTS: Liver regeneration after 70% hepatectomy was significantly suppressed in the PGC-1α transgenic mice. In addition, a decrease in the blood BCAA concentration and a decrease in the liver glycogen content after 70% hepatectomy were observed in the PGC-1α transgenic mice. By administering BCAA before and after surgery, it was clarified that a significant increase in the blood BCAA concentration was observed and the liver regeneration rate was improved in the PGC-1α transgenic mice. CONCLUSIONS: BCAA administration may improve the suppression of liver regeneration in patients with sarcopenia.

Usefulness of the preoperative inflammation-based prognostic score and the ratio of visceral fat area to psoas muscle area on predicting survival for surgically resected adenocarcinoma of the esophagogastric junction.

BACKGROUND: Sarcopenic obesity is associated with gastrointestinal cancer prognosis through systemic inflammation. However, in patients with adenocarcinoma of the esophagogastric junction (AEG), the relationship between the inflammation-based prognostic score (IBPS), muscle loss, visceral fat mass, and prognosis has not been sufficiently evaluated. We investigated the prognostic value of the preoperative IBPS and the visceral fat area ratio to the psoas muscle area (V/P ratio) in patients with AEG undergoing surgery. METHODS: We retrospectively analyzed 92 patients with AEG who underwent surgery. The prognostic value of the preoperative neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio, systemic inflammation response index, C-reactive protein-to-albumin ratio, prognostic nutritional index, modified Glasgow Prognostic Score, and V/P ratio at the third lumbar vertebra was investigated using univariate and multivariate survival analyses. RESULTS: Multivariate analysis revealed that a high pathological stage (p = 0.0065), high PLR (p = 0.0421), and low V/P ratio (p = 0.0053) were independent prognostic factors for poor overall survival (OS). When restricted to patients with body mass index (BMI) ≥ 25 kg/m2, a high V/P ratio was a poor prognostic factor (p = 0.0463) for OS. Conversely, when restricted to patients with BMI < 25 kg/m2, a low V/P ratio was a poor prognostic factor (p = 0.0021) for OS. CONCLUSIONS: Both PLR and V/P ratios may be useful prognostic biomarkers in surgical cases of AEG. V/P ratio and BMI may provide an accurate understanding of the muscle and fat mass's precise nature and may help predict AEG prognosis.

Association Between High Expression of Phosphorylated-STMN1 and Mesenchymal Marker Expression and Cancer Stemness in Breast Cancer.

BACKGROUND/AIM: In patients with breast cancer, the expression of stathmin1 (STMN1) has been significantly related to a poor prognosis, cancer aggressiveness, and expression of cancer stem cell markers. The STMN1 protein is closely regulated by phosphorylation in four sites. However, few studies have investigated the relationship between the expression of phosphorylated STMN1 (pSTMN1) and clinicopathological findings, including tumor-aggressive biomarkers, in patients with breast cancer. MATERIALS AND METHODS: The expression levels of four pSTMN1 (Ser16, Ser25, Ser38, and Ser63) were immunohistochemically analyzed in 213 breast cancer cases. The clinicopathological factors evaluated included epithelial-mesenchymal transition (EMT) markers and cancer stem cell markers. RESULTS: The cytoplasmic expression of pSTMN1 (Ser16, Ser25, Ser38, and Ser63) in normal breast tissues was low. The positive expression ratios of Ser25 (54.5%) and Ser38 (39.0%) were high compared to those of Ser16 (25.8%) and Ser63 (23.9%). The overexpression of pSTMN1 (Ser38) was associated with tumor-aggressive characteristics, such as triple-negative breast cancer (TNBC) phenotypes, high mesenchymal marker, and expression of cancer stem cell markers. CONCLUSION: STMN1 phosphorylation might be associated with clinicopathological factors, breast cancer subtypes, and expression of mesenchymal markers and breast cancer stem cell markers through the regulation of STMN1 function. Ser38 phosphorylation of STMN1 may be a novel biomarker for high-grade TNBC associated with mesenchymal marker expression and cancer stemness.

HLA Class I Expression Is Associated with DNA Damage and Immune Cell Infiltration into Dysplastic and Neoplastic Lesions in Ulcerative Colitis.

Human leukocyte antigen class I (HLA-I) is considered a genetic pathogen for ulcerative colitis (UC). This study aimed to investigate the significance of DNA damage and HLA-I expression in infiltrating immune cells and immune checkpoint protein PD-L1 expression in dysplasia/colitic cancer (CC) and sporadic colorectal cancer (SCRC). We performed immunohistochemical staining for HLA-I, PD-L1, γH2AX (DNA damage marker), and immune cell markers such as CD8, FOXP3, CD68, and CD163 (in surgically resected specimens from 17 SCRC patients with 12 adjacent normal mucosa (NM) and 9 UC patients with 18 dysplasia/CC tumors. The ratio of membrane HLA-I-positive epithelial cells in UC and dysplasia/CC tissues was significantly higher than that in NM and SCRC. High HLA-I expression in dysplasia/CC was associated with high positivity of γH2AX and PD-L1 expression compared to SCRC. The infiltration of CD8-positive T cells and CD68-positive macrophages in HLA-I-high dysplasia/CC was significantly higher than in UC and SCRC. Dysplasia/CC specimens with DNA damage exhibited high levels of HLA-I-positive epithelial cells with high CD8- and CD68-positive immune cell infiltration compared to UC and SCRC specimens. Targeting DNA damage in UC may regulate immune cell infiltration, immune checkpoint proteins, and carcinogenesis by modulating DNA damage-induced HLA-I antigen presentation.

High Tumoral STMN1 Expression Is Associated with Malignant Potential and Poor Prognosis in Patients with Neuroblastoma.

BACKGROUND: Stathmin 1 (STMN1), a marker for immature neurons and tumors, controls microtubule dynamics by destabilizing tubulin. It plays an essential role in cancer progression and indicates poor prognosis in several cancers. This potential protein has not been clarified in clinical patients with neuroblastoma. Therefore, this study aimed to assess the clinical significance and STMN1 function in neuroblastoma with and without MYCN amplification. METHODS: Using immunohistochemical staining, STMN1 expression was examined in 81 neuroblastoma samples. Functional analysis revealed the association among STMN1 suppression, cellular viability, and endogenous or exogenous MYCN expression in neuroblastoma cell lines. RESULT: High levels of STMN1 expression were associated with malignant potential, proliferation potency, and poor prognosis in neuroblastoma. STMN1 expression was an independent prognostic factor in patients with neuroblastoma. Furthermore, STMN1 knockdown inhibited neuroblastoma cell growth regardless of endogenous and exogenous MYCN overexpression. CONCLUSION: Our data suggest that assessing STMN1 expression in neuroblastoma could be a powerful indicator of prognosis and that STMN1 might be a promising therapeutic candidate against refractory neuroblastoma with and without MYCN amplification.

Significance of Lipopolysaccharides in Gastric Cancer and Their Potential as a Biomarker for Nivolumab Sensitivity.

Lipopolysaccharides are a type of polysaccharide mainly present in the bacterial outer membrane of Gram-negative bacteria. Recent studies have revealed that lipopolysaccharides contribute to the immune response of the host by functioning as a cancer antigen. We retrospectively recruited 198 patients with gastric cancer who underwent surgery. The presence of lipopolysaccharides was determined using immunohistochemical staining, with the intensity score indicating positivity. The relationship between lipopolysaccharides and CD8, PD-L1, TGFBI (a representative downstream gene of TGF-ß signaling), wnt3a, and E-cadherin (epithelial-mesenchymal transition marker) was also investigated. Thereafter, we identified 20 patients with advanced gastric cancer receiving nivolumab and investigated the relationship between lipopolysaccharides and nivolumab sensitivity. After staining for lipopolysaccharides in the nucleus of cancer cells, 150 negative (75.8%) and 48 positive cases (24.2%) were found. The lipopolysaccharide-positive group showed increased cancer stromal TGFBI expression (p < 0.0001) and PD-L1 expression in cancer cells (p = 0.0029). Lipopolysaccharide positivity was significantly correlated with increased wnt3a signaling (p = 0.0028) and decreased E-cadherin expression (p = 0.0055); however, no significant correlation was found between lipopolysaccharide expression and overall survival rate (p = 0.71). In contrast, high TGFBI expression in the presence of LPS was associated with a worse prognosis than that in the absence of LPS (p = 0.049). Among cases receiving nivolumab, the lipopolysaccharide-negative and -positive groups had disease control rates of 66.7% and 11.8%, respectively (p = 0.088). Lipopolysaccharide positivity was associated with wnt3a, TGF-ß signaling, and epithelial-mesenchymal transition and was considered to tend to promote therapeutic resistance to nivolumab.

Infiltration of Gastric Cancer Stroma by Tumor-Infiltrating Lymphocytes Correlates with Mechanistic Target of Rapamycin Signaling.

INTRODUCTION: We investigated whether the infiltration of tumor-infiltrating lymphocytes (TILs) in gastric cancer (GC), as evaluated by hematoxylin and eosin (H&E) staining, could be a prognostic marker. We also explored on the relationship between TILs and mechanistic target of rapamycin (mTOR) and how it regulates immune effector responses in GC. METHODS: A total of 183 patients with available data on TIL were included. TIL infiltration was evaluated using H&E staining. We also conducted immunohistochemistry to determine mTOR expression. RESULTS: Positive TIL infiltration was defined as TILs ≥20%. There were 72 (39.3%) and 111 (60.7%) positive and negative cases, respectively. TILs positivity significantly correlated with both absence of lymph node metastasis (p = 0.037) and negative p-mTOR expression (p = 0.040). TIL infiltration correlated with a significantly better overall (p = 0.046) and disease-free (p = 0.020) survival. CONCLUSION: mTOR possibly suppresses TIL infiltration in GC. H&E staining is an effective tool for evaluating the immune status of GC patients. H&E staining may be used in clinical practice to monitor treatment response in GC.

High RRN3 expression is associated with malignant characteristics and poor prognosis in pancreatic cancer.

BACKGROUND: Pancreatic cancer has an extremely poor prognosis and is one of the most chemoresistant cancers. Targeting cancer cell transcriptional complexes may enhance chemotherapy effectiveness. RNA-polymerase I (Pol-I)-mediated transcription is an essential initial step for ribosome biogenesis and is related to cancer cell proliferation. RRN3 is a Pol-I-specific transcription initiation factor. In this study, we aimed to elucidate the function and clinical significance of RRN3 in pancreatic cancer. METHODS: We performed immunohistochemical staining to detect RRN3 protein expression in 96 pancreatic cancer tissues and analyzed the relationship between RRN3 protein expression, clinicopathological factors, and cancer patient prognosis. Moreover, we evaluated RRN3 function in vitro and in vivo using proliferation, invasion, and chemosensitivity assays in PANC-1 and SW1990 cell lines, with/without depleting RRN3 expression. RESULTS: RRN3 was mainly expressed in cancer cell nuclei. High levels of RRN3 expression were associated with Ki-67 expression and shorter overall survival. Additionally, proliferation and invasion ability were decreased when RRN3 was silenced with siRNA, compared to non-targeting siRNA-transfected cells. Chemosensitivity analysis showed that inhibition of RRN3 enhanced the sensitivity of pancreatic cancer cell lines to gemcitabine and paclitaxel. RRN3 siRNA-transfected PANC-1 tumors showed significantly reduced tumor volumes and high gemcitabine sensitivity compared to the control in a mouse xenograft model. CONCLUSION: High levels of RRN3 expression are associated with poor prognosis and cancer malignancy, such as proliferation, invasion ability, and chemosensitivity in pancreatic cancer. RRN3 targeting with anticancer drugs may be a promising therapeutic strategy to overcome refractory pancreatic cancer.

Association of High LAT1 Expression with Poor Prognosis and Recurrence in Colorectal Cancer Patients Treated with Oxaliplatin-Based Adjuvant Chemotherapy.

The mammalian target of rapamycin (mTOR) is often activated in several cancers. We focused on two mTOR regulatory mechanisms: oxaliplatin-induced mTOR signaling and L-type amino acid transporter 1 (LAT1)-induced mTOR activation. High LAT1 expression in several cancers is associated with mTOR activation and resistance to chemotherapy. However, the significance of LAT1 has not yet been elucidated in colorectal cancer (CRC) patients treated with post-operative adjuvant chemotherapy. Immunohistochemistry was conducted to examine the significance of membrane LAT1 expression in 98 CRC patients who received adjuvant chemotherapy, including oxaliplatin. In vitro analysis was performed using CRC cell lines to determine the effects of LAT1 suppression on proliferation, oxaliplatin sensitivity, and mTOR signaling. LAT1 expression was associated with cancer aggressiveness and poor prognosis in 98 CRC patients treated with adjuvant chemotherapy. We found that positive LAT1 expression correlated with shorter survival in 43 patients treated with the capecitabine-plus-oxaliplatin (CAPOX) regimen. LAT1 suppression in CRC cells inhibited the proliferation potency and oxaliplatin-induced activation of mTOR signaling, and improved oxaliplatin sensitivity. LAT1 evaluation before adjuvant treatment may therefore be a sensitive marker for oxaliplatin-based regimens. Moreover, LAT1 may be a promising target for patients with refractory CRC.

Field carcinogenesis and biological significance of the potential of the bystander effect: carcinogenesis, therapeutic response, and tissue regeneration.

The "bystander effect" is a transmission phenomenon mediating communication from target to non-target cells, as well as cell-to-cell interactions between neighboring and distantly located cells. In this narrative review, we describe the fundamental and clinical significance of the bystander effect with respect to cell-to-cell interactions in carcinogenesis, therapeutic response, and tissue regeneration. In carcinogenesis, the bystander effect mediates communications between tumor microenvironments and non-malignant epithelial cells and has been suggested to impact heterogeneous tumorigenic cells in tumors and cancerized fields. In therapeutic response, the bystander effect mediates communications between drug-sensitive and drug-resistant cells and may transmit both drug efficacy and resistance. Therefore, control of therapeutic response transmission via the bystander effect might offer a promising future cancer treatment. Finally, in tissue regeneration, circulating cells and stromal cells may differentiate into various cells for the purpose of tissue regeneration under direction of the bystander effect arising from surrounding cells in a defective space. We hope that the findings we present will promote the development of innovative cancer therapies and tissue regeneration methodologies from the viewpoint of cell-to-cell interactions through the bystander effect.

A new liver regeneration molecular mechanism involving hepatic stellate cells, Kupffer cells, and glucose-regulated protein 78 as a new hepatotrophic factor.

BACKGROUND/PURPOSE: To overcome liver failure, we focused on liver regeneration mechanisms by the activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs). It is known that the HSC-secreted Mac-2-binding protein glycan isomer (M2BPGi) activates KC in the fibrotic liver. However, its importance for liver regeneration of the HSCs/M2BPGi/KCs axis after hepatectomy is still unknown. The aim of this study was to clarify whether the HSC-derived M2BPGi can activate KCs after hepatectomy, and elucidate the new molecular mechanism of liver regeneration. METHODS: We examined the effect of M2BPGi on human hepatocytes and KCs, and explored secretory factors from M2BPGi-activated KCs using proteomics. Furthermore, the effect on liver regeneration of glucose-regulated protein 78 (GRP78) as one of the M2BPGi-related secreted proteins was examined in vitro and in murine hepatectomy models. RESULTS: Although M2BPGi had no hepatocyte-promoting effect, M2BPGi promoted the production of GRP78 in KCs. The KC-driven GRP78 promoted hepatocyte proliferation. GRP78 administration facilitated liver regeneration after 70% hepatectomy and increased the survival rate after 90% hepatectomy in mice. CONCLUSIONS: The M2BPGi-activated KCs secrete GRP78, which facilitates liver regeneration and improves the survival in a lethal mice model. Our data suggest that the new hepatotrophic factor GRP78 may be a promising therapeutic tool for lethal liver failure.