PD1/PD-L1 blockade in clear cell renal cell carcinoma: mechanistic insights, clinical efficacy, and future perspectives.

The advent of PD1/PD-L1 inhibitors has significantly transformed the therapeutic landscape for clear cell renal cell carcinoma (ccRCC). This review provides an in-depth analysis of the biological functions and regulatory mechanisms of PD1 and PD-L1 in ccRCC, emphasizing their role in tumor immune evasion. We comprehensively evaluate the clinical efficacy and safety profiles of PD1/PD-L1 inhibitors, such as Nivolumab and Pembrolizumab, through a critical examination of recent clinical trial data. Furthermore, we discuss the challenges posed by resistance mechanisms to these therapies and potential strategies to overcome them. We also explores the synergistic potential of combination therapies, integrating PD1/PD-L1 inhibitors with other immunotherapies, targeted therapies, and conventional modalities such as chemotherapy and radiotherapy. In addition, we examine emerging predictive biomarkers for response to PD1/PD-L1 blockade and biomarkers indicative of resistance, providing a foundation for personalized therapeutic approaches. Finally, we outline future research directions, highlighting the need for novel therapeutic strategies, deeper mechanistic insights, and the development of individualized treatment regimens. Our work summarizes the latest knowledge and progress in this field, aiming to provide a valuable reference for improving clinical efficacy and guiding future research on the application of PD1/PD-L1 inhibitors in ccRCC.

CAFs and T cells interplay: The emergence of a new arena in cancer combat.

The interaction between the immune system and the tumor matrix has a huge impact on the progression and treatment of cancer. This paper summarizes and discusses the crosstalk between T cells and cancer-associated fibroblasts (CAFs). CAFs can also produce inhibitors that counteract the function of T cells and promote tumor immune escape, while T cells can also engage in complex two-way interactions with CAFs through direct cell contact, the exchange of soluble factors such as cytokines, and the remodeling of the extracellular matrix. Precise targeted intervention can effectively reverse tumor-promoting crosstalk between T cells and CAFs, improve anti-tumor immune response, and provide a new perspective for cancer treatment. Therefore, it is important to deeply understand the mechanism of crosstalk between T cells and CAFs. This review aims to outline the underlying mechanisms of these interactions and discuss potential therapeutic strategies that may become fundamental tools in the treatment of cancer, especially hard-to-cure cancers.

AK7-deficiency reversal inhibits ccRCC progression and boosts anti-PD1 immunotherapy sensitivity.

Clear cell renal cell carcinoma (ccRCC) is a common kidney cancer with subtle early symptoms, high recurrence rates, and low sensitivity to traditional treatments like radiotherapy and chemotherapy. Identifying novel therapeutic targets is critical. The expression level of adenylate kinases 7 (AK7) in ccRCC was examined by the TCGAportal and UALCAN databases. The effect of AK7 on proliferation, invasion and migration of ccRCC cell lines was evaluated by cell assay. The correlation between AK7 expression and prognosis, as well as its direct relationship with immunotherapy efficacy, was analyzed using CANCERTOOL and Kaplan-Meier plotter data. Moreover, the TISIDB database was used to study the relationship between AK7 and immune markers. The effect of overexpressed AK7 combined with PD1 monoclonal antibody on ccRCC was evaluated in animal experiments. The results showed that low level of AK7 expression was observed in ccRCC tissues. The expression of AK7 can regulate the proliferation, invasion, and migration of human ccRCC cell lines. The level of AK7 expression was associated with OS of ccRCC patients. This was potentially due to the negative connection between AK7 expression and CD8+ T cell depletion, indicating that immunotherapy might be less effective in individuals with low AK7 expression. Conversely, augmenting AK7 demonstrated an enhanced effectiveness of anti-PD1 therapy. The findings of our research strongly indicated that AK7 could serve as both a prognostic indicator and therapeutic target for patients with ccRCC. Moreover, the overexpression of AK7 combined with anti-PD1 held promising potential as a therapeutic approach for treating ccRCC.

Neuroendocrine carcinoma of the common hepatic duct coexisting with distal cholangiocarcinoma: A case report and review of literature.

BACKGROUND: Neuroendocrine carcinoma (NEC) of the extrahepatic bile duct is very rare, and the treatment and prognosis are unclear. Herein, we report the case of a middle-aged female with primary large cell NEC (LCNEC) of the common hepatic duct combined with distal cholangiocarcinoma (dCCA). Additionally, after a review of the relevant literature, we summarize and compare mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) and pure NEC to provide a reference for selecting the appropriate treatment and predicting the prognosis of this rare disease. CASE SUMMARY: A 62-year-old female presented to the hospital due to recurrent abdominal pain for 2 months. Physical examination showed mild tenderness in the upper abdomen and a positive Courvoisier sign. Blood tests showed elevated liver transaminase and carbohydrate antigen 199 levels. Imaging examination revealed a 1-cm tumour in the middle and lower segments of the common bile duct. Pancreaticoduodenectomy + lymph node dissection was performed, and hepatic duct tumours were unexpectedly found during surgery. Pathology suggested poorly differentiated LCNEC (approximately 0.5 cm × 0.5 cm × 0.4 cm), Ki-67 (50%), synaptophysin+, and chromogranin A+. dCCA pathology suggested moderately differentiated adenocarcinoma. The patient eventually developed lymph node metastasis in the liver, bone, peritoneum, and abdominal cavity and died 24 months after surgery. Gene sequencing methods were used to compare gene mutations in the two primary bile duct tumours. CONCLUSION: The prognosis of MiNEN and pure NEC alone is different, and the selection of treatment options needs to be differentiated.

Apolipoprotein E is a prognostic factor for pancreatic cancer and associates with immune infiltration.

BACKGROUND: The expression level of apolipoprotein E (APOE) in pancreatic ductal adenocarcinoma (PDAC) and its effect on the prognosis of PDAC patients are not clear. The effect of APOE on the immune status of patients with PDAC has not been elucidated. METHODS: We obtained pancreatic cancer data from the TCGA and GETx databases. Patients with PDAC who underwent pancreatic surgery at the Second Affiliated Hospital of Jiaxing University between 2012 and 2021 were included. Clinical pathological data were recorded, plasma APOE levels were measured, and tissue samples were collected. A tissue microarray was generated using the collected tissue samples. APOE and CD4 staining was performed to determine immunoreactive scores (IRSs). The expression of APOE in the plasma and tumour tissues of pancreatic cancer patients was analysed and compared. The correlations between plasma APOE levels, tissue APOE levels and clinicopathological characteristics were analysed. Survival prognosis was analysed using Kaplan-Meier survival analysis and Cox multivariate regression analysis. The correlations between APOE expression levels and immune biomarkers and immune cells were further analysed. Single-cell analysis of APOE distribution in various cells was performed on the TISCH website. RESULTS: APOE was highly expressed in the tumour tissue of pancreatic cancer patients, and high plasma APOE levels were associated with poor prognosis. Females, patients with high-grade disease and patients with pancreatic head carcinoma had high plasma APOE levels. High APOE expression in tumour tissues was associated with good prognosis. Mononuclear macrophages in the pancreatic cancer microenvironment primarily expressed APOE. APOE levels positively correlated with immune biomarkers, such as CD8A, PDCD1, GZMA, CXCL10, and CXCL9, in the tumour microenvironment. APOE promoted CD4 + T cell or dendritic cell infiltration in the tumour microenvironment. CONCLUSIONS: APOE may affect the occurrence and development of pancreatic cancer by regulating the infiltration of immune cells in the tumour microenvironment.

Unveiling the promise of PD1/PD-L1: A new dawn in immunotherapy for cholangiocarcinoma.

Cholangiocarcinoma (CCA), a rare yet notably aggressive cancer, has experienced a surge in incidence in recent years. Presently, surgical resection remains the most effective curative strategy for CCA. Nevertheless, a majority of patients with CCA are ineligible for surgical removal at the time of diagnosis. For advanced stages of CCA, the combination of gemcitabine and cisplatin is established as the standard chemotherapy regimen. Despite this, treatment efficacy is often hindered by the development of resistance. In recent times, immune checkpoint inhibitors, particularly those that block programmed death 1 and its ligand (PD1/PD-L1), have emerged as promising strategies against a variety of cancers and are being increasingly integrated into the therapeutic landscape of CCA. A growing body of research supports that the use of PD1/PD-L1 monoclonal antibodies in conjunction with chemotherapy may significantly improve patient outcomes. This article seeks to meticulously review the latest studies on PD1/PD-L1 involvement in CCA, delving into their expression profiles, prognostic significance, contribution to oncogenic processes, and their potential clinical utility.

miR-101-3p-mediated role of PDZK1 in hepatocellular carcinoma progression and the underlying PI3K/Akt signaling mechanism.

BACKGROUND: The molecular targets and associated mechanisms of hepatocellular carcinoma (HCC) have been widely studied, but the roles of PDZK1 in HCC are unclear. Therefore, the aim of this study is to explore the role and associated mechanisms of PDZK1 in HCC. RESULTS: It was found that the expression of PDZK1 in HCC tissues was higher than that in paired paracancerous tissues. High expression of PDZK1 was associated with lymph node metastasis, degree of differentiation, and clinical stage. Upregulation of PDZK1 in HCC cells affected their proliferation, migration, invasion, apoptosis, and cell cycle, and also induced PI3K/AKT activation. PDZK1 is a downstream target gene of miR-101-3p. Accordingly, increase in the expression of miR-101-3p reversed the promotive effect of PDZK1 in HCC. Moreover, PDZK1 was found to accelerate cell proliferation and promote the malignant progression of HCC via the PI3K/AKT pathway. CONCLUSION: Our study indicated that the miR-101-3p/PDZK1 axis plays a role in HCC progression and could be beneficial as a novel biomarker and new therapeutic target for HCC treatment.

Triterpene acid from Antrodia camphorata alleviates inflammation in acute liver injury.

This study aimed to investigate the role and mechanism of Anctin A, the Antrodia camphorata terpene component, in resisting liver injury. Network pharmacology analysis revealed that MAPK3 was the major action target of Antcin A. Furthermore, experimental research suggested that Antcin A suppressed mouse liver injury, reduced the inflammatory factor levels, and enhanced the anti-oxidative capacity. Meanwhile, it suppressed the expression of MAPK3 and the downstream NF-κB signal, while it did not significantly affect the expression of MAPK1. Based on network pharmacology method, this study discovers that the anti-liver injury effect of Antcin A is mainly related to MAPK3, and that Antcin A can suppress the activation of MAPK3 and its downstream NF-κB to inhibit mouse ALI.

PCSK6 mediates Th1 differentiation and promotes chronic colitis progression and mucosal barrier injury via STAT1.

This study was aimed at investigating the expression and role of proprotein convertase subtilisin/kexin type (PCSK6) in inflammatory bowel disease (IBD). DSS induced mouse colitis and mucosal barrier injury, down-regulation of TJ proteins, improvement of permeability, and increases of the proportions of Th1 and M1 macrophages. After PCSK6 knockdown, the colitis in KO mice was improved relative to WT mice, the TJ protein levels increased, and the proportions of Th1 and M1 macrophages decreased. STAT1 inhibitor treatment also inhibited chronic colitis in mice. As revealed by in-vitro experiments, PCSK6 overexpression promoted the transformation of Th0 into Th1, while PCSK6 silencing suppressed the transfection. COPI assay results revealed the presence of targeted binding relation between PCSK6 and STAT1. PCSK6 binds to STAT1 to promote STAT1 phosphorylation and regulate Th1 cell differentiation, thus promoting the M1 polarization of macrophages and aggravating colitis progression. PCSK6 is promising as the new target for the treatment of colitis.

LncRNA MALAT1 regulates METTL3-mediated PD-L1 expression and immune infiltrates in pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer death in the United States. The main methods of treating pancreatic cancer are surgery and chemotherapy, but the treatment efficacy is low with a poor prognosis. Immunotherapy represented by PD-1/PD-L1 has brought a milestone progress in the treatment of pancreatic cancer. However, the unique tumor microenvironment of pancreatic cancer presents challenges for immunotherapy. In addition, m6A is a common RNA modification and a potential molecular target in tumor therapy. The expression pattern of m6A in pancreatic cancer is still unclear. LncRNAs also play an essential role in pancreatic cancer development and treatment. In this study, we found that some m6A regulators were significantly elevated in pancreatic cancer and associated with the expression of PD-1/PD-L1. Moreover, we observed that METTL3 can increase the expression of PD-L1. Notably, METTL3 positively regulates the expression of lncRNA MALAT1 in pancreatic cancer cells. Strikingly, lncRNA MALAT1 increased the expression of PD-L1 in pancreatic cancer cells. This finding indicated that METTL3 regulated the expression of PD-L1 possibly via targeting lncRNA MALAT1 in pancreatic cancer cells. Lastly, MALAT1 governed the viability of pancreatic cancer cells. Taken together, lncRNA MALAT1 is involved in METTL3-mediated promotion of PD-L1 expression in pancreatic cancer.

[Corrigendum] 7­Difluoromethoxyl­5,4'­di­n­octyl genistein inhibits the stem­like characteristics of gastric cancer stem­like cells and reverses the phenotype of epithelial­mesenchymal transition in gastric cancer cells.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that there appeared to be two pairs of images in Fig. 2A and B on p. 1159 and Fig. 4 on p. 1161 that contained overlapping sections, such that these figures, which were intending to show the results from differently performed experiments, may have been derived from the same original sources. The authors have examined their original data, and realize that, although Fig. 2 was correct as presented in the article, these data were erroneously and inadvertently included in Fig. 4. The revised version of Fig. 4, which shows the inhibition of sphere­forming ability by 7­difluoromethoxyl­5,4'­di­n­octyl genistein (DOFG) in gastric cancer stem­like cells derived from SGC­7901 cells, is shown below, now including the correct data for the panels showing treatment with 0 and 1.0 µmol/l DOFG, and with re­quantification of these data. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish a Corrigendum, and all the authors agree with its publication. Furthermore, they apologize to the readership for any inconvenience caused. [Oncology Reports 36: 1157­1165, 2016; DOI: 10.3892/or.2016.4848].

Clinical prognostic value of circulating tumor cells in the treatment of pancreatic cancer with gemcitabine chemotherapy.

Pancreatic cancer (PC) is a highly malignant tumor type with a high early metastasis rate and no obvious symptoms. Gemcitabine is a first-line chemotherapeutic drug for PC. Since there is no distinct method to determine the efficacy of chemotherapy with gemcitabine in patients with PC, the purpose of the present study was to determine whether positivity for circulating tumor cells (CTCs) in patients with advanced PC is associated with response to gemcitabine chemotherapy and to explore whether CTCs may be used as a predictor of prognosis of patients with advanced PC undergoing chemotherapy. First, immunomagnetic microspheres (magnetic beads; MIL) were prepared to detect CTCs. The patients' clinical characteristics and survival data, as well as efficacy and adverse effects of chemotherapy, were prospectively obtained and their association with CTCs was analyzed. The results indicated that CTC-positive patients with advanced PC had a higher probability of developing resistance to gemcitabine chemotherapy than CTC-negative patients. Survival in the CTC-negative group was significantly higher than in the CTC-positive group (χ2=14.58, P<0.001). CTC-positive patients with advanced PC also had shorter progression-free survival (PFS) after chemotherapy with gemcitabine (P=0.01). In conclusion, CTC-positive patients with PC are more likely to develop gemcitabine resistance, have poor PFS and low incidence of thrombocytopenia. CTCs are expected to become a prognostic indicator for chemotherapy response in patients with PC.

MicroRNA-148a-3p Directly Targets SERPINE1 to Suppress EMT-Mediated Colon Adenocarcinoma Progression.

AIM: This research aimed at clarifying the intracellular effect of SERPINE1 in the progression of colon adenocarcinoma (COAD) and the underlying mechanism. METHODS: We obtained the expression profile of SERPINE1 in COAD via the Starbase database and verified it on COAD tissue samples through qRT-PCR and immunoblotting, respectively. Also, miRWalk, TargetScan and miRDB databases were adopted to generate the miRNA prediction that might target SERPINE1, and the gene target miR-148a-3p was confirmed using dual-luciferase assays. The effect of SERPINE1 and miR-148a-3p on COAD was further evaluated by cell experiments. MTT assay was used to detect the change of cell proliferation ability. The invasive and migratory capability of COAD cells was examined using transwell and would healing assays. Cell apoptosis was determined through flow cytometry. The expressions of genes and EMT-associated proteins were evaluated by qRT-PCR and immunoblotting. Further lucubration of the biological relevance of SERPINE1 and miR-148a-3p was conducted using rescue experiments. RESULTS: We found that the expression quantities of SERPINE1 in COAD tissues and cell lines were higher than those in corresponding non-cancerous tissues and normal cells. When SERPINE1 expression is reduced, EMT process is inhibited, invasion and proliferation ability of COAD cells are obviously reduced, and apoptosis level is increased. Moreover, SERPINE1 was identified as the target gene of miR-148a-3p. When the expression of miR-148a-3p was enhanced, it was found that the expression of SERPINE1 was reduced. miR-148a-3p played the similar effect of si-SERPINE1 that suppressed the COAD progression. Additionally, we found out that SERPINE1 is validated in hindering the tumor healing effect of miR148a-3p in COAD, including cell growth and invasion. CONCLUSION: Our study suggests that SERPINE1/miR-148a-3p axis has potential as prognostic markers of COAD and provides reference for the development of new therapies.

MicroRNA­642a­5p inhibits colon cancer cell migration and invasion by targeting collagen type I α1.

The aim of the present study was to explore the mechanism by which microRNA (miR)­642a­5p regulates the migration and invasion of colon cancer cells via collagen type I α1 (COL1A1). The characteristics of miR­642a­5p and COL1A1 were analysed through bioinformatics. Cancer and normal tissues were collected from patients with colon cancer. miR­642a­5p­ and COL1A1­overexpressing cell lines were constructed by transfection. A dual­luciferase reporter assay was used to verify the targeting of COL1A1 by miR­642a­5p. Cell Counting Kit­8, wound healing and Transwell assays were used to detect cell viability, migration and invasion, respectively. Protein and mRNA expression levels were examined by western blotting and reverse transcription­quantitative PCR, respectively. The results revealed that miR­642a­5p expression was significantly upregulated and COL1A1 expression was downregulated in patients with colon cancer. Low levels of miR­642a­5p and high levels of COL1A1 were associated with a poor prognosis in patients with colon cancer. miR­642a­5p directly targeted the 3'­untranslated region of COL1A1 and inhibited COL1A1 expression. Overexpression of miR­642a­5p inhibited cell viability, migration, invasion and epithelial mesenchymal transition. Overexpression of COL1A1 promoted cell viability, migration, invasion and EMT, and partially reversed the inhibitory effects of miR­642a­5p on colon cancer cells. In conclusion, miR­642a­5p inhibited colon cancer cell migration, invasion and EMT by regulating COL1A1.

Hepatitis B Virus Reactivation Potential Risk Factors in Hepatocellular Carcinoma via Transcatheter Arterial Chemoembolization: A Retrospective Research.

Background: To explore the clinical characteristics of reactivation of hepatitis B virus (HBV) in hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). The pathological correlation of prognosis and hepatitis B virus reactivation has been given detailed analyses in our research. Methods: A total of 108 related TACE-treated HCC clinical data from January 2008 to January 2016 was gleaned and involved in this retrospective analysis. To lucubrate the nuance of survival rates between HBV reactivated group and HBV nonreactivated group, clinical data of each patient was analyzed in detail and refined the retrospective studies. Results: HBV reactivation occurred in 42 patients with a proportion of 38.9%. The detected HBV DNA level ≥104 in patients showed a reactivation rate of 65.8% (25/38), which was significantly higher than the HBV DNA < 104 cases (24.3%, 17/70). Research data revealed a conspicuous lower cellular immunity (P < 0.01) and better 2-year survival rate (P=0.03) in the HBV-reactivated group when compared to the nonreactivated group. Conclusion: Some of the patients with primary hepatocellular carcinoma possibly had HBV reactivation at post-TACE-therapy. And the predominant risk factors of HBV reactivation are positive HBV test and immunosuppression. Our study suggested that HBV reactivation at post-TACE-therapy is an independent predictor of poor prognosis and low survival rate as well as a crucial reason for poor prognosis and lower survival rate, which indirectly proved that it is urgent to necessitate the antiviral therapy and immune enhancer in improving the curative effect and prognosis of HCC patients.

AMP­activated protein kinase family member 5 is an independent prognostic indicator of pancreatic adenocarcinoma: A study based on The Cancer Genome Atlas.

Pancreatic adenocarcinoma (PAAD) is a common and highly malignant tumor. The identification of prognostic biomarkers for PAAD could provide invaluable information for clinical treatment. AMP­activated protein kinase family member 5 (ARK5) is a member of the AMPK family that mediates the migration of PAAD cells. In the present study, ARK5 expression was evaluated using bioinformatics analysis in public datasets from The Cancer Genome Atlas. The expression levels of ARK5 in PAAD tumor tissue were significantly increased, compared with matched non­cancerous tissues. ARK5 target genes were then predicted and Gene Ontology Biological Processes, Kyoto Encyclopedia of Genes and Genomes pathway analysis and Reactome gene sets were used to determine the functions associated with the target genes. A protein­protein interaction network was also constructed to find out the node genes and observe their association with the overall survival rate of PAAD. A total of nine node genes were identified in the PPI network, of which six were significantly upregulated in PAAD tissue, compared with matched normal tissue. The prognostic value of each node gene was evaluated by comparing the overall survival in patients with PAAD stratified according to the expression levels of these genes. Overall survival was significantly reduced in patients with high polo­like kinase­1 (PLK1) or protein phosphatase 1 catalytic subunit ß (PPP1CB) expression, compared with patients with low expression of these genes. To further evaluate the relationship between PAAD and ARK5, ARK5 immunohistochemical staining was performed in a tissue microarray consisting of 112 tumor samples from patients with PAAD and adjacent normal tissue samples. ARK5 protein expression in PAAD tissue was markedly increased, compared with non­cancerous tissue (P=7.631x10­11). Moreover, ARK5 protein levels were associated with N stage (P=0.018). The overall survival of patients with PAAD with high ARK5 protein expression levels was reduced (P=0.014), compared with patients with low expression. In conclusion, these findings suggested that ARK5 may represent an independent prognostic indicator of PAAD.

Novel three­lncRNA signature predicts survival in patients with pancreatic cancer.

A growing body of evidence confirms that long non­coding RNAs (lncRNAs) have an important role in biological processes by regulating gene expression at multiple levels. Dysregulated lncRNAs may be potential prognostic biomarkers or targets for the development of cancer treatments. However, the prognostic role of an lncRNA signature in pancreatic cancer has not been investigated. Pancreatic cancer lncRNA expression profiles from The Cancer Genome Atlas (TCGA) were analyzed in the current study. The prognostic value of differentially expressed lncRNAs (DElncRNAs) was evaluated via the Kaplan­Meier method. A risk score model was established based on the potential prognostic lncRNAs. The biological functions of lncRNAs were predicted by functional enrichment analysis. Then, an lncRNA­mRNA co­expression network was established and predicted the function of the lncRNAs. Seven DElncRNAs that were significantly associated with the prognosis of pancreatic cancer were identified. Patients were classified into high­risk and low­risk groups using a risk score based on a three­lncRNA signature. There was a significant difference in overall survival (OS) between the groups (median OS 1.33 vs. 3.65 years; log­rank test, P=0.0000). Cox regression analysis and ROC curves demonstrated that the three­lncRNA signature may be an effective independent prognostic biomarker in patients with pancreatic. The functional enrichment analysis showed that lncRNA AL137789.1, one component of the three­lncRNA signature, may be associated with tumor immune responses. In the present study, a novel three­lncRNA signature that was established that may be useful in predicting survival among patients with pancreatic cancer. These lncRNAs may be involved in tumor immunity and thus affect the prognosis of patients.

AMPK-related kinase 5 (ARK5) enhances gemcitabine resistance in pancreatic carcinoma by inducing epithelial-mesenchymal transition.

AMPK-related kinase 5 (ARK5) is a member of the human AMP-activated protein kinase (AMPK) family, which is associated with increased tumor survival and drug resistance in many cancers. However, the function of ARK5 in pancreatic carcinoma (PC) is unclear. Our study investigated the role of ARK5 in the chemo-resistance of PC and its underlying mechanism. PC cell lines that displayed high expression levels of ARK5 had low sensitivity to gemcitabine (GEM). Suppression of ARK5 increased sensitivity to GEM in PC cell lines. Western blotting and immunofluorescence showed that suppression of ARK5 upregulated expression of E-cadherin and downregulated vimentin expression. Suppression of ARK5 also inhibited the epithelial-mesenchymal transition (EMT) efficiency associated with GEM in PC cell lines and upregulation of ARK5 expression enhanced GEM resistance in PC cell lines by inducing Twist-mediated EMT. In addition, we found that suppression of ARK5 increased GEM sensitivity in PC cell lines under hypoxic conditions. ARK5 increases GEM resistance in PC cell lines via EMT, and suppression of ARK5 increases sensitivity to GEM under both normoxic and hypoxic conditions.