A Rare Case of Pleural Epithelioid Mesothelioma With a Prominent Myxoid Stroma Reported With Morphology, Fluorescent In Situ Hybridization, and Ultrastructural Findings.

Herein, we report a rare case of pleural epithelioid malignant mesothelioma with a prominent myxoid stroma. To date, detailed morphological or molecular pathological findings have not been reported for this type of tumor. Hence, we aimed to describe the cytological, histological, immuno-cytohistological, electron-microscopic, and molecular pathological findings using fluorescence in situ hybridization (FISH) in such a case. The patient was a male in his mid-sixties with a history of asbestos exposure and had originally visited the hospital with a persistent cough and fever. Chest radiography revealed left pleural effusion, and laboratory examination revealed a high titer for hyaluronic acid in the effusion. Additionally, computed tomography revealed diffuse multinodular or cystic lesions in the left parietal pleura, and pleural effusion cytology revealed large epithelioid cells with mild nuclear atypia, which were considered reactive mesothelial cells. Cytologically, Giemsa staining revealed that these cells harbored variously sized intracytoplasmic vacuoles that were Alcian-blue-positive, suggesting hyaluronan production. Biopsy revealed large epithelioid cells that loosely proliferated against a prominent myxoid background. These cells were immuno-positive for calretinin, Wilms' tumor 1, D2-40, vimentin, and cytokeratin AE1/AE3 but not for carcinoembryonic antigen, Ber-EP4, or desmin. BRCA 1 associated protein 1 immunostaining showed nuclear loss, and FISH showed homozygous deletion of cyclin-dependent kinase inhibitor 2A (p16) on chromosome 9p21. Based on these findings, the lesion was diagnosed as an epithelioid mesothelioma with a prominent myxoid stroma. Electron-microscopy demonstrated a dense microvillus pattern on the surface of the tumor cells, indicating a mesothelial cell origin, and variously sized vacuoles in the cytoplasm, confirming the presence of intracytoplasmic vacuoles demonstrated on cytology. The tumor tissues obtained during surgery harbored prominent myxoid stroma, which proved that the present tumor was consistent with this type of mesothelioma. After informed consent was obtained, the patient and family wished for total resection of the tumor and postoperative chemotherapy, and the patient eventually died eight months after surgery.

Atypical lymphoplasmacytic and immunoblastic proliferation: A Systematic Review.

Atypical lymphoplasmacytic and immunoblastic proliferation (ALPIBP) was first reported in 1984 as characteristic histological findings in lymph nodes associated with autoimmune diseases, but it has not been clearly defined to date. To summarize the histological characteristics and clinical diagnoses associated with ALPIBP, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including "atypical lymphoplasmacytic and immunoblastic lymphadenopathy" from their inception to December 27, 2023. We also summarized the courses of three cases with a pathological diagnosis of ALPIBP. Nine articles with 52 cases were included. Among the total of 55 cases, including the three from our institution, the median age of the cases was 63.5 years with a female predominance (69.5%). Lymphadenopathy was generalized in 65.6% and regional in 34.4% of cases. RA (24.4%), SLE (24.4%), and autoimmune hemolytic anemia (20.0%), were common clinical diagnoses. A combination of cytotoxic chemotherapy was used in 15.6% of cases due to the suspicion of malignancy. Nodal T-follicular helper cell lymphoma, angioimmunoblastic type, methotrexate-associated lymphoproliferative disorders, and IgG4-related diseases were listed as important diseases that need to be pathologically differentiated from ALPIBP. This review summarizes the current understanding of the characteristics of ALPIBP. Given that underrecognition of ALPIBP could lead to overdiagnosis of hematological malignancy and unnecessary treatment, increased awareness of the condition in pathologists and clinicians is crucial.

Oncogenic Targets Regulated by Tumor-Suppressive miR-30c-1-3p and miR-30c-2-3p: TRIP13 Facilitates Cancer Cell Aggressiveness in Breast Cancer.

Accumulating evidence suggests that the miR-30 family act as critical players (tumor-suppressor or oncogenic) in a wide range of human cancers. Analysis of microRNA (miRNA) expression signatures and The Cancer Genome Atlas (TCGA) database revealed that that two passenger strand miRNAs, miR-30c-1-3p and miR-30c-2-3p, were downregulated in cancer tissues, and their low expression was closely associated with worse prognosis in patients with BrCa. Functional assays showed that miR-30c-1-3p and miR-30c-2-3p overexpression significantly inhibited cancer cell aggressiveness, suggesting these two miRNAs acted as tumor-suppressors in BrCa cells. Notably, involvement of passenger strands of miRNAs is a new concept of cancer research. Further analyses showed that seven genes (TRIP13, CCNB1, RAD51, PSPH, CENPN, KPNA2, and MXRA5) were putative targets of miR-30c-1-3p and miR-30c-2-3p in BrCa cells. Expression of seven genes were upregulated in BrCa tissues and predicted a worse prognosis of the patients. Among these genes, we focused on TRIP13 and investigated the functional significance of this gene in BrCa cells. Luciferase reporter assays showed that TRIP13 was directly regulated by these two miRNAs. TRIP13 knockdown using siRNA attenuated BrCa cell aggressiveness. Inactivation of TRIP13 using a specific inhibitor prevented the malignant transformation of BrCa cells. Exploring the molecular networks controlled by miRNAs, including passenger strands, will facilitate the identification of diagnostic markers and therapeutic target molecules in BrCa.

Modification of oncoplastic breast surgery with immediate volume replacement using a thoracodorsal adipofascial flap.

BACKGROUND: The treatment of early breast cancer using breast conservation therapy (BCT) commonly ensures local control and acceptable cosmetic results. We report a useful technique including the use of a thoracodorsal adipofascial cutaneous flap for reconstructing defects in the outer quadrant area after partial mastectomy, which achieved excellent results. METHODS: During the past 15 years, some modifications have been added to the original method at a rate of one modification every 2-5 years. We classified these modifications into the original method and four modified methods. Modification I: addition of a crescent-shaped dermis on the distant edge of the thoracodorsal adipofascial flap (TDAFF), Modification II: addition of a crescent-shaped dermis on the proximal edge of the TDAFF, Modification III: addition of inframammary formation plus Modification II, and Modification IV: change of a crescent-shaped dermis to a Benz-shaped (shaped like the Mercedes Benz logo) one plus Modification III. We compared the plastic period, postoperative complications, oncological results, and cosmetic results among the original and four modified groups. RESULTS: The patient number was 26, 9, 15, 23, and 10 in the original and Modification I, II, III, and IV groups, respectively. The median observation period was 115, 92, 67, 51, and 32 months, respectively. Postoperative complications were seen in 5 (19%), 0, 2 (13%), 1 (5%), and 0 patients, respectively. Local recurrence was seen in 3 (12%), 0, 0, 0, and 0 patients, respectively. Distant recurrence was seen in 1 (4%), 1 (11%), 3 (20%), 0, and 0 patients, respectively. Cosmetic results evaluated as good-excellent were seen in 19 (73%), 5 (56%), 11 (73%), 19 (83%), and 10 (100%) patients, respectively. CONCLUSIONS: Oncoplastic surgery using an immediate volume replacement technique with a thoracodorsal adipofascial flap was improved by adding some modifications.

Oncoplastic breast surgery combining partial mastectomy with resection of double equilateral triangular skin flaps.

The treatment of early breast cancer using oncoplastic breast surgery (OBS) has been gradually increasing in popularity and is recognized for its efficacy in local control and excellent cosmetic results. We herein report a useful technique for obtaining symmetry of the breast shape for an early breast lesion located in an outer area, close to the nipple-areola, in a Japanese patient with ptotic, fatty breasts. We designed two equilateral triangles: one just upon the resected area and the other on the axilla. They were located on a straight line, with one top pointed to the cranial side and one to the caudal side. A crescent area around the areola was de-epithelialized in the 12 o'clock and 6 o'clock directions. Columnar-shaped breast tissue and an equilateral triangular skin flap and fatty tissue were removed together. To fill the defect, a skin-glandular flap was slid horizontally after suturing the inframammary line. Although an incision scar was formed on the breast and lateral chest wall in a Z-shape, this new technique was able to achieve not only cancer control but also excellent cosmetic results.

RNA-Sequencing Based microRNA Expression Signature of Colorectal Cancer: The Impact of Oncogenic Targets Regulated by miR-490-3p.

To elucidate novel aspects of the molecular pathogenesis of colorectal cancer (CRC), we have created a new microRNA (miRNA) expression signature based on RNA-sequencing. Analysis of the signature showed that 84 miRNAs were upregulated, and 70 were downregulated in CRC tissues. Interestingly, our signature indicated that both guide and passenger strands of some miRNAs were significantly dysregulated in CRC tissues. These findings support our earlier data demonstrating the involvement of miRNA passenger strands in cancer pathogenesis. Our study focused on downregulated miR-490-3p and investigated its tumor-suppressive function in CRC cells. We successfully identified a total of 38 putative oncogenic targets regulated by miR-490-3p in CRC cells. Among these targets, the expression of three genes (IRAK1: p = 0.0427, FUT1: p = 0.0468, and GPRIN2: p = 0.0080) significantly predicted 5-year overall survival of CRC patients. Moreover, we analyzed the direct regulation of IRAK1 by miR-490-3p, and its resultant oncogenic function in CRC cells. Thus, we have clarified a part of the molecular pathway of CRC based on the action of tumor-suppressive miR-490-3p. This new miRNA expression signature of CRC will be a useful tool for elucidating new molecular pathogenesis in this disease.

Colorectal Cancer Patients Have Four Specific Bacterial Species in Oral and Gut Microbiota in Common-A Metagenomic Comparison with Healthy Subjects.

Oral microbiota is reportedly associated with gut microbiota and influences colorectal cancer (CRC) progression; however, the details remain unclear. This study aimed to evaluate the role of oral microbiota in CRC progression. Fifty-two patients with CRC and 51 healthy controls were included. Saliva and stool samples were collected, and microbiota were evaluated using 16S rRNA analysis and next-generation sequencing. Comparative analysis was performed on both groups. Linear discriminant analysis effect size (LEfSe) revealed the presence of indigenous oral bacteria, such as Peptostreptococcus, Streptococcus, and Solobacterium spp., at a significantly higher relative abundance in saliva and stool samples of CRC patients compared with controls. Next, CRC patients were divided into early stage (Stage I, II; n = 26; 50%) and advanced stage (Stage III, IV; n = 26; 50%) disease. LEfSe revealed that S. moorei was present at a significantly higher relative abundance in the advanced-stage group compared with the early-stage group, again consistent for both saliva and stool samples. Among bacterial species with significantly higher relative abundance in CRC patients, P. stomatis, S. anginosus, S. koreensis, and S. moorei originated from the oral cavity, suggesting indigenous oral bacteria may have promoted initiation of CRC carcinogenesis. Furthermore, S. moorei may influence CRC progression.

Immediate breast reconstruction with expander following recurrent lesion resection and exchange to silicon breast implant in a pregnant triple negative breast cancer patient: case report.

A 39-year-old gravida 1 para 1 pregnant Japanese woman underwent skin-sparing mastectomy and axillary lymph node dissection with immediate breast reconstruction (IBR) using a tissue expander (TE) at 32 weeks of pregnancy under general anesthesia. Inserted TE (300 cc) was expanded during breast feeding while the volume was 240 cc of the resected breast tissue. One month after delivery, 2 months after surgery, the contralateral healthy breast increased in size and the inframammary line was deviated toward a caudal site which was larger than 300 cc-inflated TE. She stopped breast feeding to receive a systemic chemotherapy after one months-breast feeding. At 3 months after delivery, the healthy breast size was smaller than the 250 cc-expanded breast and both the inframammary lines were at the same level. She was diagnosed local recurrence 3 month-postoperatively, so we resected the recurrent lesion and exchanged TE to silicon breast implant immediately. Finally, a good symmetry was obtained after insertion of the 220 cc SBI. At an IBR using TE, we should know the dynamic change of breast volume and the level of inframammary line of the healthy breast during those phases of pregnancy, delivery, and nursing.

[A Case of an Elderly Frail Patient with Unresectable Colorectal Cancer Controlled by Trifluridine/Tipiracil with Bevacizumab Therapy as a First-Line Treatment].

Although the effectiveness of trifluridine/tipiracil(TFTD)with bevacizumab for unresectable colorectal cancer that was refractory to previous standard chemotherapy was reported, its effectiveness as a first-line treatment, especially for elderly frail patients, is unclear. An 85-year-old woman complaining of anorexia was diagnosed with unresectable sigmoid colon cancer with multiple metastases. Her general status was very poor, and her performance status(PS)was 4. We first performed laparoscopic transverse colostomy. As her general status gradually improved, we administered TFTD with bevacizumab as a first-line treatment based on the patient's strong request for chemotherapy. The patient underwent this regimen in the outpatient clinic for 9 months(9 courses). Although the size of the liver metastases increased, lung metastases and abdominal disseminations were under control and her PS became 0. She has been taking mFOLFOX6 with bevacizumab (80%)as a second-line treatment. TFTD with bevacizumab treatment was safe and efficacious as a first-line treatment for a frail elderly patient with unresectable colorectal cancer.

Oncoplastic breast surgery combining partial mastectomy with V-rotation mammoplasty for breast cancer on the upper inner area of the breast.

The treatment of early breast cancer using breast conservation therapy (BCT) commonly ensures local control and acceptable cosmetic results. We herein report a useful technique for obtaining symmetry of the breast shape and a level inframammary line and nipple-areola that achieved excellent results. Four Japanese patients with early breast cancer located on the upper inner area of the breast were enrolled into this study. De-epithelialized skin close to the resected area and skin from the epigastric area with subdermal fatty tissue were moved to repair the defect. Oncoplastic breast surgery (OBS) combining partial mastectomy with the V-rotation mammoplasty technique was useful for patients with breast cancer on the upper inner area of minimal ptotic breasts.

Molecular pathogenesis of breast cancer: impact of miR-99a-5p and miR-99a-3p regulation on oncogenic genes.

Our recent research has revealed that passenger strands of certain microRNAs (miRNAs) function as tumor-suppressive miRNAs in cancer cells, e.g., miR-101-5p, miR-143-5p, miR-144-5p, miR-145-3p, and miR-150-3p. Thus, they are important in cancer pathogenesis. Analysis of the miRNA expression signature of breast cancer (BrCa) showed that the expression levels of two miRNAs derived from pre-miR-99a (miR-99a-5p and miR-99a-3p) were suppressed in cancerous tissues. The aim of this study was to identify oncogenic genes controlled by pre-miR-99a that are closely involved in the molecular pathogenesis of BrCa. A total of 113 genes were identified as targets of pre-miR-99a regulation (19 genes modulated by miR-99a-5p, and 95 genes regulated by miR-99a-3p) in BrCa cells. Notably, FAM64A was targeted by both of the miRNAs. Among these targets, high expression of 16 genes (C5orf22, YOD1, SLBP, F11R, C12orf49, SRPK1, ZNF250, ZNF695, CDK1, DNMT3B, TRIM25, MCM4, CDKN3, PRPS, FAM64A, and DESI2) significantly predicted reduced survival of BrCa patients based upon The Cancer Genome Atlas (TCGA) database. In this study, we focused on FAM64A and investigated the relationship between FAM64A expression and molecular pathogenesis of BrCa subtypes. The upregulation of FAM64A was confirmed in BrCa clinical specimens. Importantly, the expression of FAM64A significantly differed between patients with Luminal-A and Luminal-B subtypes. Our data strongly suggest that the aberrant expression of FAM64A is involved in the malignant transformation of BrCa. Our miRNA-based approaches (identification of tumor-suppressive miRNAs and their controlled targets) will provide novel information regarding the molecular pathogenesis of BrCa.

Oncoplastic breast surgery combining partial mastectomy with a triangular skin resection and re-centralization of the nipple-areola.

The treatment of early breast cancer using breast conservation therapy (BCT) commonly ensures local control and acceptable cosmetic results. We herein report a useful technique to obtain symmetry of the breast shape and a level inframammary line and nipple-areola, which achieved excellent results. Six Japanese patients with early breast cancer located on the upper area of the breast were enrolled into this study. A triangle-shaped area of skin was removed together with cancerous and healthy-surrounding breast tissue. Two crescents were designed and de-epithelialized in the directions of 9 o'clock and 3 o'clock. The width of the crescent was decided to be the same as a half or the length of the base of a triangle to be removed. After partial mastectomy, the inner and outer glandular flaps were horizontally sutured. The operations were simple to perform and were not associated with any postoperative complications. Oncoplastic breast surgery combining partial mastectomy with triangular skin resection and re-centralization of the nipple-areola was useful for patients with breast cancer on the upper quadrant area of non-ptotic breasts.

Juvenile Granulosa Cell Tumor with an Unusual Clinical Course: A Late-onset and Late Recurrent Case.

Juvenile granulosa cell tumors (JGCTs) are rare ovarian tumors with overall good prognoses. They differ from adult granulosa cell tumors (AGCTs), which are well known for late recurrence. Most JGCTs (～97%) occur in individuals <30 years old. We report a recurrent JGCT in a 40-year-old woman 5 years after initial presentation. The histological appearance and lack of 402C>G missense point mutation of FOXL2 gene (characteristic of AGCT but absent in JGCT) allowed differentiation from AGCT. This is the first comprehensive report of JGCT with late recurrence. Although rare, late recurrence of JGCT can occur; long-term surveillance is suggested.

Multiple liver metastases with synchronous gastric and transverse colon cancer diagnosed by gastric perforation successfully treated by SOX plus bevacizumab and completely resected by surgery: a case report.

BACKGROUND: Synchronous double cancer of the colon and stomach accompanied by liver metastasis is rare. It is often difficult to determine an appropriate treatment strategy for multiple liver metastases of synchronous gastric cancer and colorectal cancer. Multidisciplinary treatment is required based on the progression and location of each tumor and chemotherapy for complete resection. CASE PRESENTATION: A 57-year-old male who complained of acute abdominal pain and fever visited his local hospital. He underwent emergent surgery for peritonitis caused by a gastric perforation. The cytodiagnosis of ascites did not show any tumor cells. There was a liver metastasis in the lateral segment of the liver. We performed a primary closure of the defect and then applied an omentum flap. After surgery, the patient was diagnosed as having synchronous cStage IV transverse colon cancer with multiple liver metastases and cStage IIB gastric cancer. The [18F]-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) showed 18F-FDG uptake by the colon tumor and multiple liver metastases, but there was no uptake in the gastric tumor or lymph nodes. We retrospectively reevaluated the CT findings from a local hospital and detected a liver nodule in segment 2/3 (from 35 to 60 mm) and segment 6 (from 26 to 57 mm), and the tumors had dramatically grown in size in only 2 months. Because complete tumor resection would be difficult, S-1 and oxaliplatin (SOX) plus bevacizumab therapy was started to control tumor progression. After 20 courses of chemotherapy, the clinical diagnosis was ycStage IV transverse colon cancer and ycStage IIa gastric cancer. We planned a two-step procedure to completely resect the primary tumors and multiple liver metastases. We first performed a laparoscopic right-colon resection+D3 lymphadenectomy and open distal gastrectomy+D2 lymphadenectomy. The patient was discharged home on postoperative day 18. After 1 month, we performed open liver resection. The pathological findings showed that the transverse colon was ypT2 (MP) with grade 2 therapeutic effects and that there were no atypical cells in the gastric tumor and multiple liver nodules (pathological complete response). CONCLUSION: The SOX plus bevacizumab regimen could be an option for controlling tumor progression in synchronous double cancer of the colon and stomach with liver metastasis and led to the complete resection of such tumors.

RNA-sequence-based microRNA expression signature in breast cancer: tumor-suppressive miR-101-5p regulates molecular pathogenesis.

Aberrantly expressed microRNA (miRNA) are known to disrupt intracellular RNA networks in cancer cells. Exploring miRNA-dependent molecular networks is a major challenge in cancer research. In this study, we performed RNA-sequencing of breast cancer (BrCa) clinical specimens to identify tumor-suppressive miRNA in BrCa. In total, 64 miRNA were identified as candidate tumor-suppressive miRNA in BrCa cells. Analysis of our BrCa signature revealed that several miRNA duplexes (guide strand/passenger strand) derived from pre-miRNA were downregulated in BrCa tissues (e.g. miR-99a-5p/-3p, miR-101-5p/-3p, miR-126-5p/-3p, miR-143-5p/-3p, and miR-144-5p/-3p). Among these miRNA, we focused on miR-101-5p, the passenger strand of pre-miR-101, and investigated its tumor-suppressive roles and oncogenic targets in BrCa cells. Low expression of miR-101-5p predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0316). Ectopic expression of miR-101-5p attenuated aggressive phenotypes, e.g. proliferation, migration, and invasion, in BrCa cells. Finally, we identified seven putative oncogenic genes (i.e. High Mobility Group Box 3, Epithelial splicing regulatory protein 1, GINS complex subunit 1 (GINS1), Tumor Protein D52, Serine/Arginine-Rich Splicing Factor Kinase 1, Vang-like protein 1, and Mago Homolog B) regulated by miR-101-5p in BrCa cells. The expression of these target genes was associated with the molecular pathogenesis of BrCa. Furthermore, we explored the oncogenic roles of GINS1, whose function had not been previously elucidated, in BrCa cells. Aberrant expression of GINS1 mRNA and protein was observed in BrCa clinical specimens, and high GINS1 expression significantly predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0126). Knockdown of GINS1 inhibited the malignant features of BrCa cells. Thus, identification of tumor-suppressive miRNA and molecular networks controlled by these miRNA in BrCa cells may be an effective strategy for elucidation of the molecular pathogenesis of this disease.

Upgraded bidirectional approach video-assisted neck surgery (BAVANS) using a rigid endoscope with variable viewing direction for advanced endoscopic lymph node dissection in thyroid cancer patients.

In 2011, we developed bidirectional approach video-assisted neck surgery (BAVANS) for endoscopic thyroid cancer surgery. BAVANS combines two different approach pathways at 180 degrees to the cervical lesion for endoscopic thyroidectomy and complete cervical lymphadenectomy. We reported previously that the cranio-caudal approach is extremely useful for endoscopic complete lymph node dissection around the trachea. In 2014, we upgraded the initial BAVANS for better maneuverability and quality of lymph node dissection. A new high-tech rigid endoscope with a variable viewing direction (EndoCAMeleon™), has enabled us to reduce the camera port in the anterior neck while keeping the easy maneuverability and the same quality of central lymph node dissection (LND) as with the initial BAVANS. Endoscopic thyroid cancer surgery is now evolving concurrently with new visual technology.

Gene regulation by antitumor miR-130b-5p in pancreatic ductal adenocarcinoma: the clinical significance of oncogenic EPS8.

Our ongoing analyses identifying dysregulated microRNAs (miRNAs) and their controlled target RNAs have shed light on novel oncogenic pathways in pancreatic ductal adenocarcinoma (PDAC). The PDAC miRNA signature obtained by RNA sequencing showed that both strands of pre-miR-130b (miR-130b-5p, the passenger strand and miR-130b-3p, the guide strand) were significantly downregulated in cancer tissues. Our functional assays revealed that miR-130b-5p significantly blocked the malignant abilities of PDAC cell lines (PANC-1 and SW1990), e.g., cancer cell proliferation, migration, and invasion. A total of 103 genes were identified as possible oncogenic targets by miR-130b-5p regulation in PDAC cells based on genome-wide gene expression analysis and in silico database search. Among the possible targets, high expression of 9 genes (EPS8, ZWINT, SMC4, LDHA, GJB2, ZCCHC24, TOP2A, ANLN, and ADCY3) predicted a significantly poorer prognosis of PDAC patients (5-year overall survival, p < 0.001). Furthermore, we focused on EPS8 because its expression had the greatest impact on patient prognosis (overall survival, p < 0.0001). Overexpression of EPS8 was detected in PDAC clinical specimens. Knockdown assays with siEPS8 showed that its overexpression enhanced cancer cell proliferation, migration, and invasion. Analysis of downstream RNA networks regulated by EPS8 indicated that MET, HMGA2, FERMT1, RARRES3, PTK2, MAD2L1, and FLI1 were closely involved in PDAC pathogenesis. Genes regulated by antitumor miR-130b-5p were closely involved in PDAC molecular pathogenesis. Our approach, discovery of antitumor miRNAs and their target RNAs, will contribute to exploring the causes of this malignant disease.

Gene Regulation by Antitumor miR-204-5p in Pancreatic Ductal Adenocarcinoma: The Clinical Significance of Direct RACGAP1 Regulation.

Previously, we established a microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) tissues using RNA sequencing and found significantly reduced expression of miR-204-5p. Here, we aimed to investigate the functional significance of miR-204-5p and to identify miR-204-5p target genes involved in PDAC pathogenesis. Cancer cell migration and invasion were significantly inhibited by ectopic expression of miR-204-5p in PDAC cells. Comprehensive gene expression analyses and in silico database searches revealed 25 putative targets regulated by miR-204-5p in PDAC cells. Among these target genes, high expression levels of RACGAP1, DHRS9, AP1S3, FOXC1, PRP11, RHBDL2 and MUC4 were significant predictors of a poor prognosis of patients with PDAC. In this study, we focused on RACGAP1 (Rac guanosine triphosphatase-activating protein 1) because its expression was most significantly predictive of PDAC pathogenesis (overall survival rate: p = 0.0000548; disease-free survival rate: p = 0.0014). Overexpression of RACGAP1 was detected in PDAC clinical specimens, and its expression enhanced the migration and invasion of PDAC cells. Moreover, downstream genes affected by RACGAP1 (e.g., MMP28, CEP55, CDK1, ANLN and S100A14) are involved in PDAC pathogenesis. Our strategy to identify antitumor miRNAs and their target genes will help elucidate the molecular pathogenesis of PDAC.

Molecular pathogenesis of triple-negative breast cancer based on microRNA expression signatures: antitumor miR-204-5p targets AP1S3.

Triple-negative breast cancer (TNBC) is an aggressive type of cancer associated with a poor prognosis. Identification of novel therapeutic targets in TNBC is urgently needed. Here, we investigated the microRNA (miRNA) expression signature of TNBC using clinical specimens. In total, 104 miRNAs (56 upregulated and 48 downregulated) were significantly dysregulated in TNBC tissues; miR-204-5p showed the most dramatic downregulation. We then examined the antitumor roles of miR-204-5p in breast cancer (BC) cells. Notably, cancer cell migration and invasion were significantly reduced by ectopic expression of miR-204-5p in BC cells. Genome-wide gene expression analysis and in silico database search revealed that 32 genes were putative miR-204-5p targets. High expression of AP1S3, RACGAP1, ELOVL6, and LRRC59 was significantly associated with poor prognosis in patients with BC, and adaptor-related protein complex 1 sigma 3 subunit (AP1S3) was directly regulated by miR-204-5p, as demonstrated by luciferase reporter assays. AP1S3 overexpression was detected in TNBC clinical specimens and enhanced cancer cell aggressiveness. We further analyzed downstream RNA networks regulated by AP1S3 in BC cells. Overall, this miRNA signature is expected to be an effective tool for identification of miRNA-mediated molecular mechanisms of TNBC pathogenesis.