Summary Downregulation of the miR-143/145 microRNA (miRNA) cluster has been repeatedly reported in colon cancer and other epithelial tumors. In addition, overexpression of these miRNAs inhibits tumorigenesis, leading to broad consensus that they function as cell-autonomous epithelial tumor suppressors. We generated mice with deletion of miR-143/145 to investigate the functions of these miRNAs in intestinal physiology and disease in vivo. While intestinal development proceeded normally in the absence of these miRNAs, epithelial regeneration after injury was dramatically impaired. Surprisingly, we found that miR-143/145 are expressed and function exclusively within the mesenchymal compartment of intestine. Defective epithelial regeneration in miR-143/145-deficient mice resulted from dysfunction of smooth muscle and myofibroblasts and was associated with de-repression of the novel miR-143 target Igfbp5, which impaired IGF signaling after epithelial injury. These results provide important insights into the regulation of epithelial wound healing and argue against a cell-autonomous tumor suppressor role for miR-143/145 in colon cancer.

The cyclooxygenase-2 (COX-2) enzyme catalyzes the rate-limiting step of prostaglandin formation in inflammatory states, and COX-2 overexpression plays a key role in carcinogenesis. To understand the mechanisms regulating COX-2 expression, we examined its posttranscriptional regulation mediated through the AU-rich element (ARE) within the COX-2 mRNA 3′-untranslated region (3′UTR). RNA binding studies, performed to identify ARE-binding regulatory factors, demonstrated binding of the translational repressor protein TIA-1 to COX-2 mRNA. The significance of TIA-1-mediated regulation of COX-2 expression was observed in TIA-1 null fibroblasts that produced significantly more COX-2 protein than wild-type fibroblasts. However, TIA-1 deficiency did not alter COX-2 transcription or mRNA turnover. Colon cancer cells demonstrated to overexpress COX-2 through increased polysome association with COX-2 mRNA also showed defective TIA-1 binding both in vitro and in vivo. These findings implicate that TIA-1 functions as a translational silencer of COX-2 expression and support the hypothesis that dysregulated RNA-binding of TIA-1 promotes COX-2 expression in neoplasia.

The goal of this review is to outline some of the important surgical issues surrounding the management of patients with early (T1/T2 and N0), as well as locally advanced (T3/T4 and/or N1) rectal cancer. Surgery for rectal cancer continues to develop towards the ultimate goals of improved local control and overall survival, maintaining quality of life, and preserving sphincter, genitourinary, and sexual function. Information concerning the depth of tumor penetration through the rectal wall, lymph node involvement, and presence of distant metastatic disease is of crucial importance when planning a curative rectal cancer resection. Preoperative staging is used to determine the indication for neoadjuvant therapy as well as the indication for local excision versus radical cancer resection. Local excision is likely to be curative in most patients with a primary tumor which is limited to the submucosa (T1N0M0), without high-risk features and in the absence of metastatic disease. In appropriate patients, minimally invasive procedures, such as local excision, TEM, and laparoscopic resection allow for improved patient comfort, shorter hospital stays, and earlier return to preoperative activity level. Once the tumor invades the muscularis propria (T2), radical rectal resection in acceptable operative candidates is recommended. In patients with transmural and/or node positive disease (T3/T4 and/or N1) with no distant metastases, preoperative chemoradiation followed by radical resection according to the principles of TME has become widely accepted. During the planning and conduct of a radical operation for a locally advanced rectal cancer, a number of surgical management issues are considered, including: (1) total mesorectal excision (TME); (2) autonomic nerve preservation (ANP); (3) circumferential resection margin (CRM); (4) distal resection margin; (5) sphincter preservation and options for restoration of bowel continuity; (6) laparoscopic approaches; and (7) postoperative quality of life.

Margin status is an important prognostic factor for local recurrence after partial mastectomy for breast malignancy. Options for intraoperative evaluation of margin status include gross examination of the specimen, frozen section, and “touch preparation” cytology. This study evaluates the accuracy of gross examination without other intraoperative pathological analysis as a method of determining margin status. Records of 254 consecutive patients undergoing partial mastectomy for 255 breast malignancies (199 invasive, 56 DCIS) over 6 years were analyzed retrospectively. All women underwent en bloc excision of the primary lesion with gross examination of margin status by the surgeon and pathologist. All suspicious areas were reexcised, and the specimen was inked, serially sectioned at 2–3 mm intervals and examined with hematoxylin and eosin (H&E) stains. Specimens with tumor <2 mm from a margin were considered margin-positive and those with all tumor ≥2 mm from the margin were designated margin-negative. One hundred fourteen (45%) of the 255 segmental resections were considered to have grossly tumor-free margins, and intraoperative reexcision was not performed. Ninety-six (84%) of these specimens had histologically negative margins. Gross examination prompted intraoperative reexcision in 141 (55%) cases. Ninety-five (67%) of these 141 resections had tumor-free margins on histopathology. Overall, the final margin was involved in 64 of the 255 partial mastectomies. Seventeen (27%) women with initially margin-positive resections underwent mastectomy, while 46 (72%) underwent reexcision, which was margin-negative in 41 (89%). After a median follow-up of 42 months, there have been eight (3.5%) local recurrences. The initial margin-positive rate was similar in ductal carcinoma in situ (DCIS) (30%) and invasive carcinoma (24%). Margin status was correlated with nodal status; there was no correlation with age, tumor size, grade hormone receptor status, or type of diagnostic biopsy. Gross examination of the resection specimen does not reflect margin status in at least 25 per cent of women undergoing partial mastectomy for breast malignancy. Other techniques for evaluation of margin status should be considered to reduce the need for reexcision of involved margins. We are currently designing a prospective clinical trial to examine the efficacy of new techniques for intraoperative evaluation of margin status.

Down-regulation of miR-26 family members has been implicated in the pathogenesis of multiple malignancies. In some settings, including glioma, however, miR-26-mediated repression of PTEN promotes tumorigenesis. To investigate the contexts in which the tumor suppressor versus oncogenic activity of miR-26 predominates in vivo, we generated miR-26a transgenic mice. Despite measureable repression of Pten, elevated miR-26a levels were not associated with malignancy in transgenic animals. We documented reduced miR-26 expression in human colorectal cancer and, accordingly, showed that miR-26a expression potently suppressed intestinal adenoma formation in Apc min/+ mice, a model known to be sensitive to Pten dosage. These studies reveal a tumor suppressor role for miR-26 in intestinal cancer that overrides putative oncogenic activity, highlighting the therapeutic potential of miR-26 delivery to this tumor type.