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Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed human cancers in the world and the fourth leading cause of cancer-related death. In this study, we found that BAI1-associated protein 2-like 2 (BAIAP2L2) was upregulated in HCC tissues and was an independent risk factor for overall survival in HCC patients. BAIAP2L2 promoted cell proliferation, stem cell activity, and cell cycle progression and inhibited apoptosis in HCC. In addition, BAIAP2L2 enhanced HCC metastasis and activated the EMT pathway. At the molecular level, NFκB1 stimulated BAIAP2L2 transcription by binding directly to its promoter region. BAIAP2L2 interacted with GABPB1 to inhibit its ubiquitin-mediated degradation and promote its nuclear translocation. Moreover, BAIAP2L2 regulated telomerase reverse transcriptase (TERT) by upregulating GABPB1 and subsequently promoted cancer properties in HCC. Collectively, our study reveals the function and mechanism of BAIAP2L2 in HCC and provides a potential biomarker and therapeutic target for HCC.

Background and aims The development and progression of hepatocellular carcinoma (HCC) is dependent on its local microenvironment. Tumor-associated macrophages (TAMs) are deemed a key factor for the tumor microenvironment and attribute to contribute to tumor aggressiveness. However, the detailed mechanism underlying the pro-metastatic effect of TAMs on HCC remains undefined. Approach and results The present study proved that TAMs were enriched in HCC. TAMs were characterized by an M2-polarized phenotype and accelerated the migratory potential of HCC cells in vitro and in vivo. Furthermore, we found that M2-derived exosomes induced TAM-mediated pro-migratory activity. With the use of mass spectrometry, we identified that integrin, αM β2 (CD11b/CD18), was notably specific and efficient in M2 macrophage-derived exosomes (M2 exos). Blocking either CD11b and/or CD18 elicited a significant decrease in M2 exos-mediated HCC cell metastasis. Mechanistically, M2 exos mediated an intercellular transfer of the CD11b/CD18, activating the matrix metalloproteinase-9 signaling pathway in recipient HCC cells to support tumor migration. Conclusions Collectively, the exosome-mediated transfer of functional CD11b/CD18 protein from TAMs to tumor cells may have the potency to boost the migratory potential of HCC cells, thus providing insights into the mechanism of tumor metastasis.

Nanomedicines generally suffer from poor accumulation in tumor cells, low anti-tumor efficacy, and drug resistance. In order to address these problems, we introduced a novel nanomedicine based on dual anti-cancer drugs, which showed good cell nuclear accumulation properties. The novel nanomedicine consisted of three components: (1) dual anti-cancer drugs, 10-hydroxycamptothecin (HCPT) and chlorambucil (CRB), whose targets are located in the cell nucleus, (2) a nuclear localizing dodecapeptide, PMI peptide (TSFAEYWNLLSP), which could activate p53 by binding with MDM2 and MDMX located in the cell nucleus, and (3) an efficient self-assembling tripeptide FFY. Our nanomedicine exhibited enhanced cellular uptake and nuclear accumulation properties, thus achieving an excellent anti-cancer capacity both in vitro and in vivo. Our study will provide an inspiration for the development of novel multifunctional nanomaterials for cancer diagnosis and therapy.

e16118 Background: The development of ICIs has promoted a major breakthrough in the field of cancer therapy. A number of patients experience primary or acquired resistance to ICIs based first line therapy. Because of the similar mechanisms, PD-(L)1 inhibitors replacement after PD-(L)1 inhibitors-based therapy resistance is difficult to sustain benefits. Therefore, whether suspending immunotherapy, or maintenance immunotherapy and switching the combination drugs in the follow-up strategy is worth to explore. Regorafenib is an oral multikinase inhibitor that blocks the activity of protein kinases involved in angiogenesis, oncogenesis and metastasis. Besides, regorafenib could regulate the immune microenvironment. This retrospective trial aims to evaluate the efficacy of regorafenib in combinations with previous ICI in advanced HCC patients who failed to previous ICI-TKI treatment. Methods: In this study, eligible patients were advanced HCC, who failed to previous treatment with TKIs and PD-1 inhibitors. 17 patients were received PD-1 inhibitor the same as the first-line treatment (dosage and mode of administration according to instructions) and regorafenib (40, 80, 120mg/m2, po, qd, d1-21) every 4 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. The primary endpoint was objective response rate (ORR), the secondly endpoints were progression-free survival (PFS), disease control rate (DCR), overall survival (OS), duration of response (DOR) and safety. Results: From Nov 15, 2020 to Jan 31, 2022, 17 patients with advanced HCC, Child-Pugh class A liver disease, and ECOG PS 0-1 (16 male vs. 1 female, 13 second-line recipients vs. 4 third-line recipients, median age of 55 years) had been enrolled. 52.94% of the patients had BCLC stage B and others had BCLC stage C. The median follow-up was 8.8 months (range, 2.7-14.7). Confirmed ORR and DCR were 41.2% and 64.7%, respectively. The median PFS was 5.21 months (95% CI, 2.65-7.77). For 13 second line patients, confirmed ORR and DCR were 46.2% and 69.2%, respectively. Median OS and DOR had not yet been reached. 12 recipients had treatment-related adverse events (TRAEs). Most frequent TEAEs (≥5%) included fatigue (15.8%), diarrhea (15.8%), periodontal disease (10.5%), hypertension (10.5%), albuminuria (5.3%). Grade 3 TRAEs occurred in 3 (17.6%) patients included gastrointestinal bleeding, hand-foot syndrome and albuminuria. No Grade 4 TRAE and new safety signal were identified. Conclusions: Regorafenib plus PD-1 inhibitor showed a promising efficacy with favorable safety in HCC patients with PD-1 inhibitor resistance, especially in the standard second line patients. Moreover, the strategy showed a higher ORR than RESORCE study (46.2% vs. 10.6%).

e16144 Background: Patients with advanced or unresectable BTC have limited treatment options and poor prognosis. The combination of ICIs with chemotherapy has demonstrated promising antitumor activity with manageable safety in the first- or second-line in treatment of patients with advanced or unresectable BTC, but only a subset of patients with BTC derive benefit. The standard systemic treatment for BTC has been gemcitabine (800-1250 mg/m2, i.v., d1 and d8, q3w) in combination with oxaliplatin/cisplatin. The regimen is associated with high frequency of intravenous injection or more hospital days. All above highlights the need for new combinations. Therefore, we conducted a retrospective trial to evaluate ICIs combined with CAPOX (more convenient dosing regimen) in patients with advanced or recurrent BTC who were treatment-naive or failed to previous treatment. Methods: In this study, eligible patients were diagnosed as unresectable advanced or recurrent BTC, therapy-naive or failed to previous treatment with chemotherapy, inhibitors of VEGFR or PD-1/PD-L1. In therapy phase, 28 patients were given with ICIs (dosage and mode of administration according to instructions, d1), oxaliplatin (130 mg/m2, i.v., d1), and capecitabine (1000mg/m2, po, bid, d1-14) every 3 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. The primary endpoint was progression-free survival (PFS), the secondly endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and adverse events (AEs). Results: From Dec 24, 2019 to Aug 6, 2021, 28 patients had been enrolled to receive therapy. The patients were characterized with a median age of 58 years (range 53-79), 75% intrahepatic cholangiocarcinoma (ICC) and 25% gallbladder cancer (GBC), 25% lymph node metastasis, 25% liver metastases, 54% with history of surgery, and 57% with therapy-native. As of Jan 23, 2022, with a median follow-up of 9.0 months (range, 2.1-23.4), safety and efficacy were assessed in 26 evaluable patients, with response of 12 PR and 6 SD. Confirmed ORR and disease control rate (DCR) were 46.2% (95% CI, 27.1%-66.2%) and 69.2% (95% CI, 48.1%-84.9%), respectively. The median PFS, median OS and median DOR were 6.1 months (95% CI, 4.9-7.3), 16.5 months (95% CI, 5.0-28.0) and 5.0 months (95% CI, 2.0-8.0), respectively. Grade 3-4 treatment-related adverse events occurred in 32.1% of patients, with thrombocytopenia and bone marrow depression ranking the most frequent. No new safety signal was identified. Conclusions: In this study, ICIs combined with CAPOX not only showed high level of safety and efficacy, but also provided convenience in the treatment of unresectable advanced or recurrent BTC.

Several studies were carried out to explore the prognostic role of neutrophil-to-lymphocyte ratio (NLR) in pancreatic cancer, however, with contradictory results. The objectives of this study were to summarize the prognostic value of NLR in pancreatic cancer. Embase, PubMed and Cochrane Library were comprehensively retrieved. All the cohort studies focusing on the prognostic value of NLR in pancreatic cancer were eligible. 37 papers containing 43 cohort studies with pancreatic cancer were finally included into this study. The results presented that patients with low NLR might have longer OS when compared to the patients with high NLR (HR = 1.81, 95%CI = 1.59-2.05, P 0.00001; I

By investigating the migration and invasion ability in pancreatic cancer, this study probed into the lncRNA MALAT1 molecular mechanism on Hippo-YAP signaling. The expression of lncRNA MALAT1 in PC tissues and cells was detected by qRT-PCR and Western blot. The effect of si-MALAT1 on proliferation was determined by CCK-8 assay. Cell apoptosis, migration, and invasion were respectively detected by flow cytometry assay, wound healing assay, and transwell assay. Western blot and immunohistochemistry were successively used for detecting LATS1 and YAP1 expression in pancreatic cancer tissues. The microarray analysis determined that lncRNA MALAT1 in pancreatic cancer was highly expressed. LncRNA MALAT1 presented an extremely high expression level in pancreatic cancer tissues and cells. After transfected with si-MALAT1, the proliferation of AsPC-1 cells decreased, induce apoptosis of AsPC-1 cells, and migration and invasion ability were reduced. The tendency of LATS1 expression level was down-regulated and YAP1 show the opposite trend in the Hippo-YAP signaling. The in vivo assay was found that the tumor to be small in size and volume, and the expression of Ki-67 was decreased. High expression of lncRNA MALAT1 in PC disorder the proliferation, apoptosis, and migration and invasion ability via influence Hippo-YAP signaling pathway.

This study was expected to reveal the regulatory effects of lncRNA UCA1 on pancreatic cancer cell progression through targeting miR-96/FOXO3. Microarray analysis was carried out on 36 cases of pancreatic cancer tissues and 16 cases of adjacent tissues among them. Expression levels of lncRNA UCA1, miR-96, and FOXO3 in pancreatic cancer tissues and cell lines were determined by qRT-PCR. Expression levels of FOXO3 protein were determined by western blot. Cell viability, cell cycle and apoptosis, cell invasion and migration were detected by CCK-8, flow cytometry, and transwell assay, respectively. The colocalization relationship between lncRNA UCA1 and miR-96 was detected by RNA FISH. Whether UCA1 could target miR-96 and whether miR-96 could target FOXO3 3'UTR were verified by dual-luciferase reporter gene assay. High expression of lncRNA UCA1 and FOXO3 and low expression of miR-96 were shown in pancreatic cancer. Inhibition of UCA1 suppressed pancreatic tumor cell proliferation, colony formation, and metastasis, while inhibition of miR-96 promoted pancreatic cancer cell progression. FOXO3 was the downstream target gene of miR-96 and showed the opposite effects. LncRNA UCA1 promoted cell proliferation, invasion, migration and inhibited cell apoptosis of pancreatic cancer through down-regulating miR-96 and up-regulating FOXO3. © 2018 IUBMB Life, 70(4):276-290, 2018.

microRNAs (miRNAs) were known as transcriptional regulators to regulate the repertoires of target genes during the development of hepatocellular carcinoma (HCC). In this study, we investigated the roles of miR-4262 in the process of HCC. Our results showed that miR-4262 is overexpressed in HCC tissues and hepatoma cell lines (HepG2 and Sk-hep-1). We also found that miR-4262 enhanced the process of cell cycle and inhibited the apoptosis leading to promoted cell proliferation and activity. Moreover, the 3'UTR of PDCD4 was complementary to miR-4262 seed region and we confirmed that PDCD4 is the direct target of miR-4262 with 3'UTR luciferase assay. qPCR and WB analysis revealed that the level of PDCD4 was negatively correlated with the expression of miR-4262 in HepG2 cells. Furthermore, our results demonstrated that miR-4262-promoted cell proliferation was mediated by PDCD4 and miR-4262 can activate the NF-κB pathway to promote the accumulation of nuclear NF-κB/P65. All of these findings suggested miR-4262 may play a role in the development of HCC.

In the present work, we undertook the complete mitochondrial genome sequencing of an important liver cancer model inbred rat strain for the first time. The total length of the mitogenome was 16,308 bp. It harbored 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 non-coding control region (D-loop region). The mutation events were also reported.