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.

We recently determined the RNA sequencing-based microRNA (miRNA) expression signature of colorectal cancer (CRC). Analysis of the signature showed that the expression of both strands of pre-miR-139 (miR-139-5p, the guide strand, and miR-139-3p, the passenger strand) was significantly reduced in CRC tissues. Transient transfection assays revealed that expression of miR-139-3p blocked cancer cell malignant transformation (e.g., cell proliferation, migration, and invasion). Notably, expression of miR-139-3p markedly blocked RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation in CRC cells. A combination of in silico database and gene expression analyses of miR-139-3p-transfected cells revealed 29 putative targets regulated by miR-139-3p in CRC cells. RNA immunoprecipitation analysis using an Argonaute2 (AGO2) antibody revealed that KRT80 was efficiently incorporated into the RNA-induced silencing complex. Aberrant expression of Keratin 80 (KRT80) was detected in CRC clinical specimens by immunostaining. A knockdown assay using small interfering RNA (siRNA) targeting KRT80 showed that reducing KRT80 expression suppressed the malignant transformation (cancer cell migration and invasion) of CRC cells. Importantly, inhibiting KRT80 expression reduced AKT phosphorylation in CRC cells. Moreover, hexokinase-2 (HK2) expression was reduced in cells transfected with the KRT80 siRNAs or miR-139-3p. The involvement of miRNA passenger strands (e.g., miR-139-3p) in CRC cells is a new concept in miRNA studies. Our tumor-suppressive miRNA-based approach helps elucidate the molecular pathogenesis of CRC.

Background Locoregional recurrence and metastasis to the liver, peritoneum, and lung are the most common recurrent patterns of pancreatic ductal adenocarcinoma (PDAC) after radical resection. Recurrence in the abdominal wall is extremely rare. Herein, we report our experience with a patient who had recurrent PDAC in the abdominal wall with long-term survival by means of multidisciplinary therapy. Case presentation A 76-year-old Japanese woman was diagnosed with resectable pancreatic tail cancer. She underwent distal pancreatectomy with regional lymphadenectomy after two cycles of gemcitabine plus S-1 as neoadjuvant therapy. She also received eight cycles of S-1 as adjuvant chemotherapy. Approximately 14 months after the initial surgery, imaging examinations identified a mass suggesting recurrence in the abdominal wall at the middle wound that involved the transverse colon. After two cycles of gemcitabine plus nab-paclitaxel, chemoradiotherapy (S-1 plus 45 Gy) and seven cycles of modified FOLFIRINOX (5-fluorouracil/leucovorin, irinotecan, and oxaliplatin) were administered. The patient did not develop any new recurrent lesions during chemotherapy and chemoradiotherapy. Therefore, the recurrent lesion in the abdominal wall and the involved transverse colon were resected. We confirmed the lack of peritoneal dissemination during surgery. Pathological examination revealed that the resected lesion was metastasis of primary PDAC, and the surgical margin was 1 mm. However, re-recurrence localized in the abdominal wall was detected 9 months later. The re-recurrent lesion was diagnosed as local recurrence of the first recurrent lesion. We performed a second resection of the abdominal wall using a femoral myocutaneous flap to achieve sufficient surgical margin. The pathological findings of the resected specimen were the same as those of the previous specimens, and the resection margin was negative. The patient’s postoperative course was uneventful. Seven years after the initial surgery and 3 years and 7 months after the third surgery, the patient is alive with no signs of recurrence. Conclusions Long-term survival could be achieved by radical resection with sufficient surgical margins for recurrence of PDAC in the abdominal wall if new other recurrent lesions, including peritoneal dissemination, are prevented through chemotherapy.

Purpose: Transanal total mesorectal excision (TaTME) for low anterior resection requires a secure anastomotic technique to avoid an anastomotic leak. This study aimed to evaluate the clinical outcomes of a novel technique of quadruple purse-string suture (PSS) for single stapling technique (SST) following TaTME. Methods: Consecutive patients who underwent TaTME with SST for rectal cancer between November 2014 and October 2020 were enrolled. Clinical outcomes of quadruple or double PSS for SST following TaTME were evaluated. The complete rates of the resection rings based on the status of the resection ring of the colonic and rectal stumps were also evaluated. Results: In total, 47 patients were included in the study: 27 and 20 in the quadruple and double PSS groups, respectively. Intraoperative adverse events occurred in one patient. The rates of postoperative complications in the quadruple and double PSS groups were 22.2% and 30.0%, respectively. The rates of anastomotic leaks in the quadruple and double PSS groups were 7.4% and 15.0%, respectively. The length of hospital stay in the quadruple and double PSS groups was 13 and 14 days, respectively. The resection ring for the rectal stump was complete in 85.2% of quadruple PSS cases and 70.0% of double PSS cases. The resection rings for both stumps were complete in 81.5% and 50.0% of patients with quadruple and double PSS, respectively (p=0.03). Conclusion: Quadruple PSS for SST following TaTME is feasible and seems to be a safe alternative to conventional double PSS in selected patients with rectal cancer.

Purpose Transanal total mesorectal excision (TaTME) remains a challenging technique for rectal dissection. This study aims to evaluate the clinical and oncological outcomes of TaTME, compared to those of the laparoscopic total mesorectal excision (LaTME) in rectal cancer. Methods Using propensity score-matched analyses, we analyzed retrospective data from 134 consecutive patients with rectal cancer who underwent TaTME or LaTME from January 2011 to June 2020 in our hospital. Clinical and oncological outcomes were evaluated. The primary endpoint was the 2-year local recurrence rate. Results Before data analysis, significant group-dependent differences were observed only in the tumor height (p < 0.01). After analysis, preoperative patients’ demographics were similar between the TaTME and LaTME-defined groups. The operative time was significantly shorter in the TaTME group (p = 0.02), and the rates of hand-sewn anastomosis and protective loop ileostomy were significantly higher(p < 0.01). TaTME showed a 29% overall morbidity rate and LaTME 44%. Furthermore, the rate of Clavien–Dindo grade III tended to be lower in the TaTME group (p = 0.07). There were no statistically significant differences in terms of pathological findings, and the 2-year local recurrence rate was similar between the two groups (both 5.9%) Conclusions TaTME based on embryology along the fascia is feasible and seems a safe alternative to LaTME in selected patients with rectal cancer when considering the conversion rate and the operative time.